15-74202177-C-T

Variant names:

• chr15-74202177-C-T
• rs111489755
• NM_022369.4:c.91G>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.91G>A​(p.Gly31Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00115 in 1,505,374 control chromosomes in the GnomAD database, including 12 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G31D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0054 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00068 (4 hom.)
• Consequence: STRA6 NM_022369.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.229
• Publications: 5 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 (MetaRNN=0.0039087236).
• BP6: Variant 15-74202177-C-T is Benign according to our data. Variant chr15-74202177-C-T is described in ClinVar as Benign. ClinVar VariationId is 317118.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 = 0.00539 (820/152164) while in subpopulation AFR AF = 0.0182 (756/41504). AF 95% confidence interval is 0.0171. There are 8 homozygotes in GnomAd4. There are 401 alleles in the male GnomAd4 subpopulation. Median coverage is 32. 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.91G>A	p.Gly31Ser	missense	Exon 2 of 19	NP_071764.3
	STRA6	NM_001199042.2		c.208G>A	p.Gly70Ser	missense	Exon 2 of 19	NP_001185971.1
	STRA6	NM_001199040.2		c.202G>A	p.Gly68Ser	missense	Exon 2 of 19	NP_001185969.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STRA6	ENST00000395105.9	TSL:1 MANE Select	c.91G>A	p.Gly31Ser	missense	Exon 2 of 19	ENSP00000378537.4
	STRA6	ENST00000563965.5	TSL:1	c.208G>A	p.Gly70Ser	missense	Exon 2 of 19	ENSP00000456609.1
	STRA6	ENST00000423167.6	TSL:1	c.91G>A	p.Gly31Ser	missense	Exon 2 of 19	ENSP00000413012.2

Frequencies

GnomAD3 genomes AF: 0.00537 AC: 816 AN: 152046 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0182

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00194

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00336

GnomAD2 exomes AF: 0.00192 AC: 333 AN: 173422 AF XY: 0.00132

Gnomad AFR exome AF: 0.0173

Gnomad AMR exome AF: 0.00117

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00205

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000199

Gnomad OTH exome AF: 0.000515

GnomAD4 exome AF: 0.000678 AC: 917 AN: 1353210 Hom.: 4 Cov.: 32 AF XY: 0.000618 AC XY: 409 AN XY: 661826

African (AFR) AF: 0.0185 AC: 553 AN: 29900

American (AMR) AF: 0.00165 AC: 46 AN: 27954

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19738

East Asian (EAS) AF: 0.00405 AC: 155 AN: 38238

South Asian (SAS) AF: 0.0000762 AC: 5 AN: 65584

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49458

Middle Eastern (MID) AF: 0.00341 AC: 18 AN: 5282

European-Non Finnish (NFE) AF: 0.0000537 AC: 57 AN: 1061480

Other (OTH) AF: 0.00149 AC: 83 AN: 55576

GnomAD4 genome AF: 0.00539 AC: 820 AN: 152164 Hom.: 8 Cov.: 32 AF XY: 0.00539 AC XY: 401 AN XY: 74384

African (AFR) AF: 0.0182 AC: 756 AN: 41504

American (AMR) AF: 0.00235 AC: 36 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00214 AC: 11 AN: 5150

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68004

Other (OTH) AF: 0.00332 AC: 7 AN: 2108

Alfa AF: 0.00216 Hom.: 6

Bravo AF: 0.00575

ESP6500AA AF: 0.0162 AC: 71

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00162 AC: 195

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Matthew-Wood syndrome (2)
-	-	1	not provided (1)
-	-	1	STRA6-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	2.9
DANN	Benign	0.79
DEOGEN2	Benign	0.028	T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.056	N
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.46	N
PhyloP100		0.23
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.12
Sift	Benign	0.41	T
Sift4G	Benign	0.64	T
Polyphen		0.019	B
Vest4		0.18
MVP		0.56
MPC		0.097
ClinPred		0.0012	T
GERP RS		2.6
PromoterAI		0.029	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.027
gMVP		0.27
Mutation Taster		=92/8	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: rs111489755; hg19: chr15-74494518; COSMIC: COSV99063599; COSMIC: COSV99063599;