15-74180114-G-A

Variant names:

• chr15-74180114-G-A
• rs144043304
• NM_022369.4:c.1970C>T

Variant summary

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

The NM_022369.4(STRA6):​c.1970C>T​(p.Thr657Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000349 in 1,613,694 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00037 (2 hom.)
• Consequence: STRA6 NM_022369.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.118
• Publications: 5 publications found

Genes affected

STRA6 (HGNC:30650): (signaling receptor and transporter of retinol STRA6) The protein encoded by this gene is a membrane protein involved in the metabolism of retinol. The encoded protein acts as a receptor for retinol/retinol binding protein complexes. This protein removes the retinol from the complex and transports it across the cell membrane. Defects in this gene are a cause of syndromic microphthalmia type 9 (MCOPS9). Several transcript variants encoding a few different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]

STRA6 Gene-Disease associations (from GenCC):

• Matthew-Wood syndrome

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• microphthalmia, isolated, with coloboma

  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 (MetaRNN=0.048727036).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000144 (22/152350) while in subpopulation SAS AF = 0.000621 (3/4830). AF 95% confidence interval is 0.000169. There are 0 homozygotes in GnomAd4. There are 10 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 2 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STRA6	NM_022369.4	c.1970C>T	p.Thr657Met	missense_variant	Exon 19 of 19	ENST00000395105.9	NP_071764.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STRA6	ENST00000395105.9	c.1970C>T	p.Thr657Met	missense_variant	Exon 19 of 19	1	NM_022369.4	ENSP00000378537.4

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152232 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000283 AC: 71 AN: 251260 AF XY: 0.000228

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000435

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000255

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000370 AC: 541 AN: 1461344 Hom.: 2 Cov.: 31 AF XY: 0.000355 AC XY: 258 AN XY: 726916

African (AFR) AF: 0.000149 AC: 5 AN: 33472

American (AMR) AF: 0.000335 AC: 15 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.000756 AC: 30 AN: 39674

South Asian (SAS) AF: 0.000487 AC: 42 AN: 86242

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53298

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5764

European-Non Finnish (NFE) AF: 0.000391 AC: 435 AN: 1111670

Other (OTH) AF: 0.000149 AC: 9 AN: 60378

GnomAD4 genome AF: 0.000144 AC: 22 AN: 152350 Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10 AN XY: 74494

African (AFR) AF: 0.0000721 AC: 3 AN: 41586

American (AMR) AF: 0.0000653 AC: 1 AN: 15310

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000250 Hom.: 0

Bravo AF: 0.000162

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000288 AC: 35

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Matthew-Wood syndrome Uncertain:2

Apr 20, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 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
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.15	T;.;T;T;.;T;.;.;.
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.053	N
LIST_S2	Benign	0.44	.;T;.;.;T;T;T;T;T
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.049	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	1.2	L;.;L;L;.;L;.;.;.
PhyloP100		-0.12
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.82	N;N;N;.;.;.;N;.;.
REVEL	Benign	0.22
Sift	Uncertain	0.029	D;D;D;.;.;.;D;.;.
Sift4G	Benign	0.095	T;T;T;T;T;T;T;T;T
Polyphen		0.65	P;P;P;P;.;P;.;P;.
Vest4		0.095
MVP		0.64
MPC		0.10
ClinPred		0.016	T
GERP RS		-0.86
Varity_R		0.014
gMVP		0.25
Mutation Taster		=97/3	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: rs144043304; hg19: chr15-74472455;