rs150814749

Variant names:

• chr15-74183933-C-T
• rs150814749
• NM_022369.4:c.1223G>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.1223G>A​(p.Arg408Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00536 in 1,613,842 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R408G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0038 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0055 (30 hom.)
• Consequence: STRA6 NM_022369.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.286
• 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=0.0045599937).
• BP6: Variant 15-74183933-C-T is Benign according to our data. Variant chr15-74183933-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 194429.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 = 0.0038 (578/152256) while in subpopulation NFE AF = 0.00678 (461/68022). AF 95% confidence interval is 0.00627. There are 4 homozygotes in GnomAd4. There are 282 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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.1223G>A	p.Arg408Gln	missense	Exon 14 of 19	NP_071764.3
	STRA6	NM_001199042.2		c.1340G>A	p.Arg447Gln	missense	Exon 14 of 19	NP_001185971.1	Q9BX79-4
	STRA6	NM_001199040.2		c.1334G>A	p.Arg445Gln	missense	Exon 14 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.1223G>A	p.Arg408Gln	missense	Exon 14 of 19	ENSP00000378537.4	Q9BX79-1
	STRA6	ENST00000563965.5	TSL:1	c.1340G>A	p.Arg447Gln	missense	Exon 14 of 19	ENSP00000456609.1	Q9BX79-4
	STRA6	ENST00000423167.6	TSL:1	c.1196G>A	p.Arg399Gln	missense	Exon 14 of 19	ENSP00000413012.2	Q9BX79-3

Frequencies

GnomAD3 genomes AF: 0.00380 AC: 578 AN: 152138 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.000942

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.00575

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00678

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00394 AC: 990 AN: 251056 AF XY: 0.00407

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00756

Gnomad NFE exome AF: 0.00647

Gnomad OTH exome AF: 0.00342

GnomAD4 exome AF: 0.00553 AC: 8076 AN: 1461586 Hom.: 30 Cov.: 30 AF XY: 0.00547 AC XY: 3978 AN XY: 727086

African (AFR) AF: 0.000926 AC: 31 AN: 33480

American (AMR) AF: 0.00103 AC: 46 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000417 AC: 36 AN: 86258

European-Finnish (FIN) AF: 0.00729 AC: 387 AN: 53116

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00655 AC: 7279 AN: 1112008

Other (OTH) AF: 0.00488 AC: 295 AN: 60396

GnomAD4 genome AF: 0.00380 AC: 578 AN: 152256 Hom.: 4 Cov.: 33 AF XY: 0.00379 AC XY: 282 AN XY: 74452

African (AFR) AF: 0.000939 AC: 39 AN: 41542

American (AMR) AF: 0.000523 AC: 8 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4818

European-Finnish (FIN) AF: 0.00575 AC: 61 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00678 AC: 461 AN: 68022

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00537 Hom.: 10

Bravo AF: 0.00304

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00791 AC: 68

ExAC AF: 0.00366 AC: 445

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00436

EpiControl AF: 0.00528

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	Matthew-Wood syndrome (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	1.9
DANN	Benign	0.57
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0054	N
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.0046	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	-0.40	N
PhyloP100		-0.29
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.32	N
REVEL	Benign	0.16
Sift	Benign	0.62	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.65
MVP		0.35
MPC		0.11
ClinPred		0.00061	T
GERP RS		-4.7
Varity_R		0.011
gMVP		0.14
Mutation Taster		=94/6	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: rs150814749; hg19: chr15-74476274; COSMIC: COSV105906074; COSMIC: COSV105906074;