chr2-61839871-A-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001201543.2(FAM161A):c.1133T>G(p.Leu378Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00352 in 1,614,172 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L378L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0038 ( 7 hom., cov: 32)

Exomes 𝑓: 0.0035 ( 22 hom. )

Consequence

FAM161A
NM_001201543.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:9

Conservation

PhyloP100: 2.17

Publications

11 publications found

Variant links:

Genes affected

FAM161A (HGNC:25808): (FAM161 centrosomal protein A) This gene belongs to the FAM161 family. It is expressed mainly in the retina. Mouse studies suggested that this gene is involved in development of retinal progenitors during embryogenesis, and that its activity is restricted to mature photoreceptors after birth. Mutations in this gene cause autosomal recessive retinitis pigmentosa-28. Alternatively spliced transcript variants have been identified.[provided by RefSeq, Jan 2011]

FAM161A Gene-Disease associations (from GenCC):

retinitis pigmentosa 28
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
retinitis pigmentosa
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

FAM161A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008030057).

BP6

Variant 2-61839871-A-C is Benign according to our data. Variant chr2-61839871-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 167058.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00378 (575/152284) while in subpopulation AMR AF = 0.00575 (88/15302). AF 95% confidence interval is 0.00478. There are 7 homozygotes in GnomAd4. There are 273 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM161A	NM_001201543.2 link	c.1133T>G	p.Leu378Arg	missense_variant	Exon 3 of 7	ENST00000404929.6	NP_001188472.1	Q3B820-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM161A	ENST00000404929.6 link	c.1133T>G	p.Leu378Arg	missense_variant	Exon 3 of 7	1	NM_001201543.2	ENSP00000385158.1		Q3B820-3

Frequencies

GnomAD3 genomes

AF:

0.00378

AC:

575

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000990

Gnomad AMI

AF:

0.0724

Gnomad AMR

AF:

0.00576

Gnomad ASJ

AF:

0.0127

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00255

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.00423

Gnomad OTH

AF:

0.00860

GnomAD2 exomes

AF:

0.00305

AC:

758

AN:

248790

AF XY:

0.00325

show subpopulations

Gnomad AFR exome

AF:

0.00103

Gnomad AMR exome

AF:

0.00261

Gnomad ASJ exome

AF:

0.00855

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00176

Gnomad NFE exome

AF:

0.00416

Gnomad OTH exome

AF:

0.00463

GnomAD4 exome

AF:

0.00349

AC:

5101

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00354

AC XY:

2574

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.000657

AC:

AN:

33480

American (AMR)

AF:

0.00300

AC:

134

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00987

AC:

258

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.000974

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00283

AC:

151

AN:

53420

Middle Eastern (MID)

AF:

0.00364

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00377

AC:

4195

AN:

1112006

Other (OTH)

AF:

0.00389

AC:

235

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

327

654

981

1308

1635

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

158

316

474

632

790

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00378

AC:

575

AN:

152284

Hom.:

Cov.:

AF XY:

0.00367

AC XY:

273

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.000987

AC:

AN:

41550

American (AMR)

AF:

0.00575

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0127

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000414

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00255

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00423

AC:

288

AN:

68026

Other (OTH)

AF:

0.00851

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

100

134

167

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00397

Hom.:

Bravo

AF:

0.00391

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.00130

AC:

ESP6500EA

AF:

0.00339

AC:

ExAC

AF:

0.00283

AC:

342

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00480

EpiControl

AF:

0.00474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:5

Nov 07, 2015

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

FAM161A: BP4, BS2 -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Retinitis pigmentosa 28

Uncertain:1Benign:2

Jun 11, 2020

Natera, Inc.

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 12, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Retinitis pigmentosa

Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified

Benign:1

Feb 18, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: FAM161A c.1133T>G (p.Leu378Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.003 in 248790 control chromosomes, predominantly within the Non-Finnish European subpopulation in the gnomAD database at a frequency of 0.0042, including 3 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database (v2.1 dataset) is approximately 6.7-fold of the estimated maximal expected allele frequency for a pathogenic variant in FAM161A causing Retinitis Pigmentosa phenotype (0.00063). The variant was also observed in the Amish subpopulation in 66/910 alleles, including 7 homozygotes, with an allele frequency of 0.0725 in the gnomAD v3.1 dataset. These data strongly suggest that the variant is a benign polymorphism. Six submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (n=3), likely benign (n=2) / benign (n=1). Based on the evidence outlined above, the variant was classified as benign. -

FAM161A-related disorder

Benign:1

Feb 19, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.17

.;T

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.42

LIST_S2

Benign

0.79

T;T

M_CAP

Benign

0.015

MetaRNN

Benign

0.0080

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.7

M;M

PhyloP100

2.2

PrimateAI

Benign

0.33

PROVEAN

Uncertain

-3.9

D;D

REVEL

Benign

0.11

Sift

Uncertain

0.0020

D;D

Sift4G

Benign

0.13

T;T

Polyphen

0.98

D;D

Vest4

0.34

MVP

0.58

MPC

0.054

ClinPred

0.070

GERP RS

-3.1

Varity_R

0.54

gMVP

0.31

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over