rs145614612

Variant names:

• chr15-74180181-C-T
• rs145614612
• NM_022369.4:c.1903G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_022369.4(STRA6):​c.1903G>A​(p.Gly635Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,613,962 control chromosomes in the GnomAD database, including 114 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0079 (8 hom., cov: 33)
  • Exomes 𝑓: 0.011 (106 hom.)
• Consequence: STRA6 NM_022369.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.683
• Publications: 6 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: Labcorp Genetics (formerly Invitae), Orphanet, G2P, PanelApp Australia
• 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 (MetaRNN=0.006873369).
• BP6: Variant 15-74180181-C-T is Benign according to our data. Variant chr15-74180181-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 317096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00791 (1204/152262) while in subpopulation NFE AF = 0.012 (817/67998). AF 95% confidence interval is 0.0113. There are 8 homozygotes in GnomAd4. There are 605 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022369.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STRA6	NM_022369.4	MANE Select	c.1903G>A	p.Gly635Ser	missense	Exon 19 of 19	NP_071764.3
	STRA6	NM_001199042.2		c.2020G>A	p.Gly674Ser	missense	Exon 19 of 19	NP_001185971.1	Q9BX79-4
	STRA6	NM_001199040.2		c.2014G>A	p.Gly672Ser	missense	Exon 19 of 19	NP_001185969.1	Q9BX79-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STRA6	ENST00000395105.9	TSL:1 MANE Select	c.1903G>A	p.Gly635Ser	missense	Exon 19 of 19	ENSP00000378537.4	Q9BX79-1
	STRA6	ENST00000563965.5	TSL:1	c.2020G>A	p.Gly674Ser	missense	Exon 19 of 19	ENSP00000456609.1	Q9BX79-4
	STRA6	ENST00000423167.6	TSL:1	c.1876G>A	p.Gly626Ser	missense	Exon 19 of 19	ENSP00000413012.2	Q9BX79-3

Frequencies

GnomAD3 genomes AF: 0.00791 AC: 1203 AN: 152144 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.00215

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00785

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00456

Gnomad FIN AF: 0.0120

Gnomad MID AF: 0.0191

Gnomad NFE AF: 0.0120

Gnomad OTH AF: 0.00766

GnomAD2 exomes AF: 0.00756 AC: 1897 AN: 250802 AF XY: 0.00795

Gnomad AFR exome AF: 0.00160

Gnomad AMR exome AF: 0.00408

Gnomad ASJ exome AF: 0.00199

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00935

Gnomad NFE exome AF: 0.0117

Gnomad OTH exome AF: 0.00540

GnomAD4 exome AF: 0.0109 AC: 15974 AN: 1461700 Hom.: 106 Cov.: 31 AF XY: 0.0108 AC XY: 7876 AN XY: 727174

African (AFR) AF: 0.00221 AC: 74 AN: 33480

American (AMR) AF: 0.00420 AC: 188 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00195 AC: 51 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00470 AC: 405 AN: 86240

European-Finnish (FIN) AF: 0.00768 AC: 409 AN: 53284

Middle Eastern (MID) AF: 0.0113 AC: 65 AN: 5768

European-Non Finnish (NFE) AF: 0.0128 AC: 14196 AN: 1111978

Other (OTH) AF: 0.00969 AC: 585 AN: 60396

GnomAD4 genome AF: 0.00791 AC: 1204 AN: 152262 Hom.: 8 Cov.: 33 AF XY: 0.00813 AC XY: 605 AN XY: 74452

African (AFR) AF: 0.00217 AC: 90 AN: 41558

American (AMR) AF: 0.00784 AC: 120 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00456 AC: 22 AN: 4822

European-Finnish (FIN) AF: 0.0120 AC: 127 AN: 10618

Middle Eastern (MID) AF: 0.0205 AC: 6 AN: 292

European-Non Finnish (NFE) AF: 0.0120 AC: 817 AN: 67998

Other (OTH) AF: 0.00758 AC: 16 AN: 2110

Alfa AF: 0.0103 Hom.: 33

Bravo AF: 0.00727

TwinsUK AF: 0.0119 AC: 44

ALSPAC AF: 0.0138 AC: 53

ESP6500AA AF: 0.00273 AC: 12

ESP6500EA AF: 0.0114 AC: 98

ExAC AF: 0.00736 AC: 894

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0136

EpiControl AF: 0.0118

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Matthew-Wood syndrome (2)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	0.057
DANN	Benign	0.86
DEOGEN2	Benign	0.084	T
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.0063	N
LIST_S2	Benign	0.52	T
MetaRNN	Benign	0.0069	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.42	N
PhyloP100		-0.68
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.84	N
REVEL	Benign	0.25
Sift	Benign	0.52	T
Sift4G	Benign	0.68	T
Polyphen		0.093	B
Vest4		0.11
MVP		0.19
MPC		0.094
ClinPred		0.00070	T
GERP RS		-4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.016
gMVP		0.21
Mutation Taster		=100/0	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: rs145614612; hg19: chr15-74472522; COSMIC: COSV99997071; COSMIC: COSV99997071;