rs11125895

Positions:

• chr2-61842223-T-C
• chr2-61842223-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001201543.2(FAM161A):​c.321A>G​(p.Ile107Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.185 in 1,612,636 control chromosomes in the GnomAD database, including 28,342 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2167 hom., cov: 32)
  • Exomes 𝑓: 0.19 (26175 hom.)
• Consequence: FAM161A NM_001201543.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.41

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0012713075).
• BP6: Variant 2-61842223-T-C is Benign according to our data. Variant chr2-61842223-T-C is described in ClinVar as [Benign]. Clinvar id is 336744.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-61842223-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.182 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAM161A	NM_001201543.2	c.321A>G	p.Ile107Met	missense_variant	2/7	ENST00000404929.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAM161A	ENST00000404929.6	c.321A>G	p.Ile107Met	missense_variant	2/7	1	NM_001201543.2	P1

Frequencies

GnomAD3 genomes AF: 0.164 AC: 24937 AN: 152084 Hom.: 2172 Cov.: 32

Gnomad AFR AF: 0.129

Gnomad AMI AF: 0.122

Gnomad AMR AF: 0.167

Gnomad ASJ AF: 0.153

Gnomad EAS AF: 0.183

Gnomad SAS AF: 0.192

Gnomad FIN AF: 0.145

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.185

Gnomad OTH AF: 0.168

GnomAD3 exomes AF: 0.182 AC: 45380 AN: 249384 Hom.: 4305 AF XY: 0.182 AC XY: 24638 AN XY: 135316

Gnomad AFR exome AF: 0.131

Gnomad AMR exome AF: 0.209

Gnomad ASJ exome AF: 0.153

Gnomad EAS exome AF: 0.177

Gnomad SAS exome AF: 0.193

Gnomad FIN exome AF: 0.147

Gnomad NFE exome AF: 0.188

Gnomad OTH exome AF: 0.187

GnomAD4 exome AF: 0.188 AC: 274156 AN: 1460434 Hom.: 26175 Cov.: 32 AF XY: 0.187 AC XY: 136033 AN XY: 726616

Gnomad4 AFR exome AF: 0.137

Gnomad4 AMR exome AF: 0.199

Gnomad4 ASJ exome AF: 0.155

Gnomad4 EAS exome AF: 0.196

Gnomad4 SAS exome AF: 0.191

Gnomad4 FIN exome AF: 0.150

Gnomad4 NFE exome AF: 0.191

Gnomad4 OTH exome AF: 0.180

GnomAD4 genome AF: 0.164 AC: 24933 AN: 152202 Hom.: 2167 Cov.: 32 AF XY: 0.162 AC XY: 12069 AN XY: 74398

Gnomad4 AFR AF: 0.128

Gnomad4 AMR AF: 0.167

Gnomad4 ASJ AF: 0.153

Gnomad4 EAS AF: 0.184

Gnomad4 SAS AF: 0.191

Gnomad4 FIN AF: 0.145

Gnomad4 NFE AF: 0.185

Gnomad4 OTH AF: 0.167

Alfa AF: 0.183 Hom.: 6632

Bravo AF: 0.166

TwinsUK AF: 0.194 AC: 718

ALSPAC AF: 0.195 AC: 752

ESP6500AA AF: 0.127 AC: 466

ESP6500EA AF: 0.186 AC: 1522

ExAC AF: 0.183 AC: 22054

Asia WGS AF: 0.194 AC: 674 AN: 3478

EpiCase AF: 0.184

EpiControl AF: 0.194

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinitis pigmentosa 28 Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 20, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Retinal dystrophy Benign:1

Benign, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Retinitis pigmentosa Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	9.7
DANN	Benign	0.71
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.58	T;T
MetaRNN	Benign	0.0013	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N;N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.21	T
PROVEAN	Benign	0.45	N;N
REVEL	Benign	0.081
Sift	Benign	0.30	T;T
Sift4G	Benign	0.29	T;T
Polyphen		0.017	B;B
Vest4		0.017
MPC		0.038
ClinPred		0.00064	T
GERP RS		1.7
Varity_R		0.057
gMVP		0.086

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

Other links and lift over

dbSNP: rs11125895; hg19: chr2-62069358; COSMIC: COSV56764403; COSMIC: COSV56764403;