rs142105038

Positions:

• chr15-74197759-G-A

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.173C>T​(p.Ser58Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00138 in 1,613,496 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0072 (16 hom., cov: 32)
  • Exomes 𝑓: 0.00077 (18 hom.)
• Consequence: STRA6 NM_022369.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.25

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=0.0072104335).
• BP6: Variant 15-74197759-G-A is Benign according to our data. Variant chr15-74197759-G-A is described in ClinVar as [Benign]. Clinvar id is 464032.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 = 0.00722 (1099/152312) while in subpopulation AFR AF= 0.0252 (1046/41566). AF 95% confidence interval is 0.0239. There are 16 homozygotes in gnomad4. There are 516 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STRA6	NM_022369.4	c.173C>T	p.Ser58Leu	missense_variant	3/19	ENST00000395105.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STRA6	ENST00000395105.9	c.173C>T	p.Ser58Leu	missense_variant	3/19	1	NM_022369.4	P1

Frequencies

GnomAD3 genomes AF: 0.00723 AC: 1101 AN: 152194 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.0253

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

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: 0.000147

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00204 AC: 509 AN: 249616 Hom.: 7 AF XY: 0.00144 AC XY: 195 AN XY: 135252

Gnomad AFR exome AF: 0.0274

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000142

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000769 AC: 1123 AN: 1461184 Hom.: 18 Cov.: 32 AF XY: 0.000634 AC XY: 461 AN XY: 726942

Gnomad4 AFR exome AF: 0.0250

Gnomad4 AMR exome AF: 0.00119

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000116

Gnomad4 OTH exome AF: 0.00154

GnomAD4 genome AF: 0.00722 AC: 1099 AN: 152312 Hom.: 16 Cov.: 32 AF XY: 0.00693 AC XY: 516 AN XY: 74464

Gnomad4 AFR AF: 0.0252

Gnomad4 AMR AF: 0.00189

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00129 Hom.: 1

Bravo AF: 0.00828

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0250 AC: 110

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00225 AC: 273

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:3

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	Dec 09, 2023	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 04, 2020

This variant is associated with the following publications: (PMID: 30653986) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T;.;T;T;.;T;.;.;.;.;.
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.017	N
MetaRNN	Benign	0.0072	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;L;L;L;.;L;.;.;.;L;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.91	N;N;N;N;.;.;N;.;.;D;.
REVEL	Benign	0.14
Sift	Benign	0.27	T;T;T;D;.;.;T;.;.;T;.
Sift4G	Benign	0.47	T;T;T;T;T;T;T;T;T;T;.
Polyphen		0.0060	B;B;B;B;.;B;.;B;.;B;.
Vest4		0.18
MVP		0.58
MPC		0.083
ClinPred		0.010	T
GERP RS		2.3
Varity_R		0.042
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs142105038; hg19: chr15-74490100;