rs115331762

chr15-74180851-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_022369.4(STRA6):c.1771G>A(p.Ala591Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00107 in 1,614,126 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0061 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00055 (16 hom.)
• Consequence: STRA6 NM_022369.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.293

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030330718).
• BP6: Variant 15-74180851-C-T is Benign according to our data. Variant chr15-74180851-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 317099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00607 (924/152304) while in subpopulation AFR AF= 0.0215 (894/41572). AF 95% confidence interval is 0.0203. There are 8 homozygotes in gnomad4. There are 438 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STRA6	NM_022369.4	c.1771G>A	p.Ala591Thr	missense_variant	18/19	ENST00000395105.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STRA6	ENST00000395105.9	c.1771G>A	p.Ala591Thr	missense_variant	18/19	1	NM_022369.4	P1

Frequencies

GnomAD3 genomes AF: 0.00604 AC: 919 AN: 152186 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0214

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

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: 0.0000147

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00155 AC: 390 AN: 251416 Hom.: 6 AF XY: 0.00103 AC XY: 140 AN XY: 135886

Gnomad AFR exome AF: 0.0227

Gnomad AMR exome AF: 0.000550

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000547 AC: 800 AN: 1461822 Hom.: 16 Cov.: 33 AF XY: 0.000430 AC XY: 313 AN XY: 727218

Gnomad4 AFR exome AF: 0.0206

Gnomad4 AMR exome AF: 0.000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.00109

GnomAD4 genome AF: 0.00607 AC: 924 AN: 152304 Hom.: 8 Cov.: 32 AF XY: 0.00588 AC XY: 438 AN XY: 74466

Gnomad4 AFR AF: 0.0215

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00425

Alfa AF: 0.000948 Hom.: 1

Bravo AF: 0.00673

ESP6500AA AF: 0.0216 AC: 95

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00206 AC: 250

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Matthew-Wood syndrome Benign:2

Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Sep 21, 2023	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 09, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 10, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	6.3
Dann	Benign	0.92
DEOGEN2	Benign	0.12	T;.;T;T;.;T;.;.;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.084	N
MetaRNN	Benign	0.0030	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N;.;N;N;.;N;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.52	N;N;N;.;.;.;N;.;.
REVEL	Benign	0.15
Sift	Benign	0.52	T;T;T;.;.;.;T;.;.
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T;T
Polyphen		0.0010	B;B;B;B;.;B;.;B;.
Vest4		0.026
MVP		0.52
MPC		0.090
ClinPred		0.0031	T
GERP RS		1.3
Varity_R		0.027
gMVP		0.063

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs115331762; hg19: chr15-74473192; COSMIC: COSV51433215; COSMIC: COSV51433215;