15-74179858-C-T

Variant names:

• chr15-74179858-C-T
• rs10910
• NM_022369.4:c.*222G>A

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.*222G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.64 in 588,096 control chromosomes in the GnomAD database, including 125,133 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (27222 hom., cov: 32)
  • Exomes 𝑓: 0.66 (97911 hom.)
• Consequence: STRA6 NM_022369.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.213
• Publications: 10 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=-0.83).
• BP6: Variant 15-74179858-C-T is Benign according to our data. Variant chr15-74179858-C-T is described in ClinVar as [Benign]. Clinvar id is 317085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.688 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STRA6	NM_022369.4	c.*222G>A		3_prime_UTR_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.*222G>A		3_prime_UTR_variant	Exon 19 of 19	1	NM_022369.4	ENSP00000378537.4

Frequencies

GnomAD3 genomes AF: 0.570 AC: 86710 AN: 152034 Hom.: 27206 Cov.: 32

Gnomad AFR AF: 0.292

Gnomad AMI AF: 0.760

Gnomad AMR AF: 0.681

Gnomad ASJ AF: 0.662

Gnomad EAS AF: 0.569

Gnomad SAS AF: 0.664

Gnomad FIN AF: 0.593

Gnomad MID AF: 0.813

Gnomad NFE AF: 0.694

Gnomad OTH AF: 0.658

GnomAD4 exome AF: 0.664 AC: 289333 AN: 435944 Hom.: 97911 Cov.: 5 AF XY: 0.666 AC XY: 150567 AN XY: 225932

African (AFR) AF: 0.286 AC: 3462 AN: 12090

American (AMR) AF: 0.657 AC: 11149 AN: 16962

Ashkenazi Jewish (ASJ) AF: 0.665 AC: 8416 AN: 12656

East Asian (EAS) AF: 0.579 AC: 16696 AN: 28842

South Asian (SAS) AF: 0.653 AC: 24405 AN: 37400

European-Finnish (FIN) AF: 0.602 AC: 16165 AN: 26850

Middle Eastern (MID) AF: 0.814 AC: 1511 AN: 1856

European-Non Finnish (NFE) AF: 0.698 AC: 191570 AN: 274552

Other (OTH) AF: 0.645 AC: 15959 AN: 24736

GnomAD4 genome AF: 0.570 AC: 86767 AN: 152152 Hom.: 27222 Cov.: 32 AF XY: 0.571 AC XY: 42494 AN XY: 74378

African (AFR) AF: 0.292 AC: 12146 AN: 41526

American (AMR) AF: 0.681 AC: 10405 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.662 AC: 2300 AN: 3472

East Asian (EAS) AF: 0.570 AC: 2946 AN: 5172

South Asian (SAS) AF: 0.665 AC: 3210 AN: 4824

European-Finnish (FIN) AF: 0.593 AC: 6278 AN: 10580

Middle Eastern (MID) AF: 0.813 AC: 239 AN: 294

European-Non Finnish (NFE) AF: 0.694 AC: 47151 AN: 67972

Other (OTH) AF: 0.662 AC: 1400 AN: 2114

Alfa AF: 0.671 Hom.: 49527

Bravo AF: 0.565

Asia WGS AF: 0.577 AC: 2010 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Matthew-Wood syndrome Benign:1

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	7.2
DANN	Benign	0.76
PhyloP100		-0.21
Mutation Taster		=100/0	polymorphism (auto)

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: rs10910; hg19: chr15-74472199; COSMIC: COSV51433327; COSMIC: COSV51433327;