2-61825838-C-T

Variant names:

• chr2-61825838-C-T
• rs188862164
• ENST00000456262.5:n.*2115G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001201543.2(FAM161A):​c.*617G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00247 in 439,506 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0059 (14 hom., cov: 31)
  • Exomes 𝑓: 0.00064 (1 hom.)
• Consequence: FAM161A NM_001201543.2 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.482
• Publications: 1 publications found

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

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00593 (902/152070) while in subpopulation AFR AF = 0.0204 (846/41458). AF 95% confidence interval is 0.0193. There are 14 homozygotes in GnomAd4. There are 437 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 14 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM161A	NM_001201543.2	c.*617G>A		3_prime_UTR_variant	Exon 7 of 7	ENST00000404929.6	NP_001188472.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM161A	ENST00000404929.6	c.*617G>A		3_prime_UTR_variant	Exon 7 of 7	1	NM_001201543.2	ENSP00000385158.1

Frequencies

GnomAD3 genomes AF: 0.00591 AC: 898 AN: 151954 Hom.: 13 Cov.: 31

Gnomad AFR AF: 0.0204

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00576

GnomAD2 exomes AF: 0.00109 AC: 128 AN: 117932 AF XY: 0.000743

Gnomad AFR exome AF: 0.0188

Gnomad AMR exome AF: 0.000809

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000220

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000640 AC: 184 AN: 287436 Hom.: 1 Cov.: 0 AF XY: 0.000428 AC XY: 70 AN XY: 163608

African (AFR) AF: 0.0189 AC: 145 AN: 7666

American (AMR) AF: 0.000741 AC: 18 AN: 24302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10214

East Asian (EAS) AF: 0.00 AC: 0 AN: 9094

South Asian (SAS) AF: 0.0000174 AC: 1 AN: 57392

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 12126

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1048

European-Non Finnish (NFE) AF: 0.0000263 AC: 4 AN: 152288

Other (OTH) AF: 0.00120 AC: 16 AN: 13306

GnomAD4 genome AF: 0.00593 AC: 902 AN: 152070 Hom.: 14 Cov.: 31 AF XY: 0.00588 AC XY: 437 AN XY: 74344

African (AFR) AF: 0.0204 AC: 846 AN: 41458

American (AMR) AF: 0.00262 AC: 40 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 67998

Other (OTH) AF: 0.00570 AC: 12 AN: 2104

Alfa AF: 0.00295 Hom.: 0

Bravo AF: 0.00667

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Retinitis pigmentosa Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.8
DANN	Benign	0.63
PhyloP100		-0.48
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs188862164; hg19: chr2-62052973;