2-61825653-T-C

Position:

• chr2-61825653-T-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_001201543.2(FAM161A):​c.*802A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00128 in 428,192 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00045 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (0 hom.)
• Consequence: FAM161A NM_001201543.2 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0290

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000448 (68/151830) while in subpopulation SAS AF= 0.0079 (38/4810). AF 95% confidence interval is 0.00592. There are 1 homozygotes in gnomad4. There are 42 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAM161A	NM_001201543.2	c.*802A>G		3_prime_UTR_variant	7/7	ENST00000404929.6	NP_001188472.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAM161A	ENST00000404929.6	c.*802A>G		3_prime_UTR_variant	7/7	1	NM_001201543.2	ENSP00000385158	P1
FAM161A	ENST00000405894.3	c.*802A>G		3_prime_UTR_variant	6/6	1		ENSP00000385893
FAM161A	ENST00000456262.5	c.*2300A>G		3_prime_UTR_variant, NMD_transcript_variant	6/6	1		ENSP00000396105
FAM161A	ENST00000418113.5	c.*1425A>G		3_prime_UTR_variant, NMD_transcript_variant	8/8	5		ENSP00000416861

Frequencies

GnomAD3 genomes AF: 0.000442 AC: 67 AN: 151720 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00768

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000295

Gnomad OTH AF: 0.00288

GnomAD3 exomes AF: 0.00163 AC: 171 AN: 104822 Hom.: 1 AF XY: 0.00177 AC XY: 102 AN XY: 57572

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000439

Gnomad ASJ exome AF: 0.00584

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00669

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000242

Gnomad OTH exome AF: 0.000312

GnomAD4 exome AF: 0.00174 AC: 481 AN: 276362 Hom.: 0 Cov.: 0 AF XY: 0.00229 AC XY: 363 AN XY: 158696

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000393

Gnomad4 ASJ exome AF: 0.00644

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00711

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000923

Gnomad4 OTH exome AF: 0.00117

GnomAD4 genome AF: 0.000448 AC: 68 AN: 151830 Hom.: 1 Cov.: 32 AF XY: 0.000566 AC XY: 42 AN XY: 74242

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00790

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000295

Gnomad4 OTH AF: 0.00285

Alfa AF: 0.000609 Hom.: 1

Bravo AF: 0.000355

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Retinitis pigmentosa Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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, 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	2.6
DANN	Benign	0.38

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: rs541819550; hg19: chr2-62052788;