2-61839437-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP5_Moderate

The NM_001201543.2(FAM161A):c.1567C>G(p.Arg523Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000156 in 1,614,004 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

FAM161A
NM_001201543.2 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 1.20

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-61839437-G-C is Pathogenic according to our data. Variant chr2-61839437-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2203076.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM161A	NM_001201543.2 link	c.1567C>G	p.Arg523Gly	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.1567C>G	p.Arg523Gly	missense_variant	Exon 3 of 7	1	NM_001201543.2	ENSP00000385158.1		Q3B820-3

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000660

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000184

AC:

AN:

249446

Hom.:

AF XY:

0.000177

AC XY:

AN XY:

135338

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000111

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00121

Gnomad NFE exome

AF:

0.000150

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000162

AC:

237

AN:

1461878

Hom.:

Cov.:

AF XY:

0.000144

AC XY:

105

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.000861

Gnomad4 NFE exome

AF:

0.000157

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152126

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74294

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000660

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000869

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000240

AC:

ExAC

AF:

0.000174

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

May 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 523 of the FAM161A protein (p.Arg523Gly). This variant is present in population databases (rs202193201, gnomAD 0.1%). This missense change has been observed in individual(s) with autosomal recessive retinitis pigmentosa (PMID: 22581970, 36819107; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 2203076). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FAM161A protein function with a positive predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Uncertain

0.042

BayesDel_noAF

Uncertain

0.080

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

.;T

Eigen

Uncertain

0.35

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.86

D;D

M_CAP

Uncertain

0.19

MetaRNN

Uncertain

0.72

D;D

MetaSVM

Benign

-0.62

MutationAssessor

Pathogenic

3.0

M;M

PrimateAI

Benign

0.44

PROVEAN

Pathogenic

-6.1

D;D

REVEL

Uncertain

0.51

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.024

D;D

Polyphen

1.0

D;D

Vest4

0.98

MVP

0.63

MPC

0.30

ClinPred

0.42

GERP RS

2.3

Varity_R

0.72

gMVP

0.37

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over