2-61825639-CT-C

Variant names:

• chr2-61825639-CT-C
• rs759062810
• ENST00000456262.5:n.*2313delA

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_001201543.2(FAM161A):​c.*815delA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.108 in 354,656 control chromosomes in the GnomAD database, including 9 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0072 (9 hom., cov: 31)
  • Exomes 𝑓: 0.17 (0 hom.)
• Consequence: FAM161A NM_001201543.2 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.158
• Publications: 0 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: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0072 (1020/141712) while in subpopulation AFR AF = 0.0188 (733/38986). AF 95% confidence interval is 0.0177. There are 9 homozygotes in GnomAd4. There are 535 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 9 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM161A	NM_001201543.2	c.*815delA		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.*815delA		3_prime_UTR_variant	Exon 7 of 7	1	NM_001201543.2	ENSP00000385158.1

Frequencies

GnomAD3 genomes AF: 0.00719 AC: 1019 AN: 141724 Hom.: 9 Cov.: 31

Gnomad AFR AF: 0.0188

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00320

Gnomad ASJ AF: 0.00568

Gnomad EAS AF: 0.00242

Gnomad SAS AF: 0.000896

Gnomad FIN AF: 0.00863

Gnomad MID AF: 0.00342

Gnomad NFE AF: 0.00189

Gnomad OTH AF: 0.00583

GnomAD2 exomes AF: 0.266 AC: 13529 AN: 50930 AF XY: 0.270

Gnomad AFR exome AF: 0.269

Gnomad AMR exome AF: 0.262

Gnomad ASJ exome AF: 0.269

Gnomad EAS exome AF: 0.253

Gnomad FIN exome AF: 0.279

Gnomad NFE exome AF: 0.262

Gnomad OTH exome AF: 0.268

GnomAD4 exome AF: 0.175 AC: 37206 AN: 212944 Hom.: 0 Cov.: 0 AF XY: 0.173 AC XY: 21252 AN XY: 122766

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.188 AC: 945 AN: 5016

American (AMR) AF: 0.184 AC: 2728 AN: 14852

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 1418 AN: 7724

East Asian (EAS) AF: 0.176 AC: 1299 AN: 7390

South Asian (SAS) AF: 0.171 AC: 7047 AN: 41296

European-Finnish (FIN) AF: 0.174 AC: 1493 AN: 8600

Middle Eastern (MID) AF: 0.178 AC: 133 AN: 746

European-Non Finnish (NFE) AF: 0.174 AC: 20396 AN: 117512

Other (OTH) AF: 0.178 AC: 1747 AN: 9808

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00720 AC: 1020 AN: 141712 Hom.: 9 Cov.: 31 AF XY: 0.00779 AC XY: 535 AN XY: 68670

African (AFR) AF: 0.0188 AC: 733 AN: 38986

American (AMR) AF: 0.00320 AC: 45 AN: 14068

Ashkenazi Jewish (ASJ) AF: 0.00568 AC: 19 AN: 3344

East Asian (EAS) AF: 0.00243 AC: 12 AN: 4940

South Asian (SAS) AF: 0.000900 AC: 4 AN: 4442

European-Finnish (FIN) AF: 0.00863 AC: 73 AN: 8462

Middle Eastern (MID) AF: 0.00373 AC: 1 AN: 268

European-Non Finnish (NFE) AF: 0.00189 AC: 122 AN: 64418

Other (OTH) AF: 0.00582 AC: 11 AN: 1890

Alfa AF: 0.0458 Hom.: 8

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Retinitis Pigmentosa, Recessive Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.16
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: rs759062810; hg19: chr2-62052774;