2-61824906-C-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001201543.2(FAM161A):c.*1549G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00417 in 450,042 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0098 (24 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (13 hom.)
• Consequence: FAM161A NM_001201543.2 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.880

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00981 (1493/152188) while in subpopulation AFR AF= 0.0346 (1438/41518). AF 95% confidence interval is 0.0331. There are 24 homozygotes in gnomad4. There are 694 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
• BS2: High Homozygotes in GnomAd at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAM161A	NM_001201543.2	c.*1549G>T		3_prime_UTR_variant	7/7	ENST00000404929.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAM161A	ENST00000404929.6	c.*1549G>T		3_prime_UTR_variant	7/7	1	NM_001201543.2	P1
FAM161A	ENST00000405894.3	c.*1549G>T		3_prime_UTR_variant	6/6	1
FAM161A	ENST00000456262.5	c.*3047G>T		3_prime_UTR_variant, NMD_transcript_variant	6/6	1
FAM161A	ENST00000418113.5	c.*2172G>T		3_prime_UTR_variant, NMD_transcript_variant	8/8	5

Frequencies

GnomAD3 genomes AF: 0.00979 AC: 1489 AN: 152070 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.0346

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00256

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00224 AC: 280 AN: 124740 Hom.: 12 AF XY: 0.00186 AC XY: 127 AN XY: 68354

Gnomad AFR exome AF: 0.0379

Gnomad AMR exome AF: 0.00170

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000234

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000646

Gnomad OTH exome AF: 0.000776

GnomAD4 exome AF: 0.00129 AC: 383 AN: 297854 Hom.: 13 Cov.: 0 AF XY: 0.00102 AC XY: 173 AN XY: 169874

Gnomad4 AFR exome AF: 0.0371

Gnomad4 AMR exome AF: 0.00178

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000154

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000570

Gnomad4 OTH exome AF: 0.000867

GnomAD4 genome AF: 0.00981 AC: 1493 AN: 152188 Hom.: 24 Cov.: 32 AF XY: 0.00933 AC XY: 694 AN XY: 74396

Gnomad4 AFR AF: 0.0346

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00523 Hom.: 0

Bravo AF: 0.0113

Asia WGS AF: 0.00260 AC: 9 AN: 3478

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	-0.69
Cadd	Benign	0.36
Dann	Benign	0.73

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: rs7563900; hg19: chr2-62052041;