chr15-74183999-G-C

Variant names:

• chr15-74183999-G-C
• rs2277608
• NM_022369.4:c.1167-10C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022369.4(STRA6):​c.1167-10C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.161 in 1,612,048 control chromosomes in the GnomAD database, including 23,597 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1928 hom., cov: 32)
  • Exomes 𝑓: 0.16 (21669 hom.)
• Consequence: STRA6 NM_022369.4 intron
• Scores: Splicing: ADA: 0.1402
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.342
• Publications: 14 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 15-74183999-G-C is Benign according to our data. Variant chr15-74183999-G-C is described in ClinVar as Benign. ClinVar VariationId is 261577.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.337 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STRA6	NM_022369.4	c.1167-10C>G		intron_variant	Intron 13 of 18	ENST00000395105.9	NP_071764.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STRA6	ENST00000395105.9	c.1167-10C>G		intron_variant	Intron 13 of 18	1	NM_022369.4	ENSP00000378537.4

Frequencies

GnomAD3 genomes AF: 0.150 AC: 22839 AN: 151968 Hom.: 1935 Cov.: 32

Gnomad AFR AF: 0.0948

Gnomad AMI AF: 0.109

Gnomad AMR AF: 0.198

Gnomad ASJ AF: 0.170

Gnomad EAS AF: 0.351

Gnomad SAS AF: 0.261

Gnomad FIN AF: 0.182

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.145

Gnomad OTH AF: 0.147

GnomAD2 exomes AF: 0.199 AC: 49696 AN: 249116 AF XY: 0.199

Gnomad AFR exome AF: 0.0871

Gnomad AMR exome AF: 0.308

Gnomad ASJ exome AF: 0.168

Gnomad EAS exome AF: 0.346

Gnomad FIN exome AF: 0.177

Gnomad NFE exome AF: 0.149

Gnomad OTH exome AF: 0.190

GnomAD4 exome AF: 0.163 AC: 237389 AN: 1459964 Hom.: 21669 Cov.: 32 AF XY: 0.166 AC XY: 120575 AN XY: 726284

African (AFR) AF: 0.0857 AC: 2869 AN: 33478

American (AMR) AF: 0.294 AC: 13151 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.174 AC: 4550 AN: 26136

East Asian (EAS) AF: 0.356 AC: 14123 AN: 39688

South Asian (SAS) AF: 0.265 AC: 22855 AN: 86250

European-Finnish (FIN) AF: 0.168 AC: 8661 AN: 51626

Middle Eastern (MID) AF: 0.183 AC: 1055 AN: 5768

European-Non Finnish (NFE) AF: 0.143 AC: 159497 AN: 1111928

Other (OTH) AF: 0.176 AC: 10628 AN: 60386

GnomAD4 genome AF: 0.150 AC: 22823 AN: 152084 Hom.: 1928 Cov.: 32 AF XY: 0.154 AC XY: 11480 AN XY: 74336

African (AFR) AF: 0.0945 AC: 3923 AN: 41508

American (AMR) AF: 0.199 AC: 3034 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.170 AC: 591 AN: 3470

East Asian (EAS) AF: 0.351 AC: 1806 AN: 5150

South Asian (SAS) AF: 0.260 AC: 1251 AN: 4814

European-Finnish (FIN) AF: 0.182 AC: 1928 AN: 10588

Middle Eastern (MID) AF: 0.188 AC: 55 AN: 292

European-Non Finnish (NFE) AF: 0.145 AC: 9831 AN: 67956

Other (OTH) AF: 0.145 AC: 305 AN: 2110

Alfa AF: 0.105 Hom.: 217

Bravo AF: 0.150

Asia WGS AF: 0.317 AC: 1100 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Matthew-Wood syndrome Benign:2

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

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 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. -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	3.4
DANN	Benign	0.73
PhyloP100		0.34
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.14
dbscSNV1_RF	Benign	0.12
SpliceAI score (max)		0.31		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.31		Position offset: -10

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2277608; hg19: chr15-74476340; COSMIC: COSV60585074; COSMIC: COSV60585074;