15-74183999-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 ENST00000395105.9(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 ENST00000395105.9 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000395105.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STRA6	NM_022369.4	MANE Select	c.1167-10C>G		intron	N/A	NP_071764.3
	STRA6	NM_001199042.2		c.1284-10C>G		intron	N/A	NP_001185971.1
	STRA6	NM_001199040.2		c.1278-10C>G		intron	N/A	NP_001185969.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STRA6	ENST00000395105.9	TSL:1 MANE Select	c.1167-10C>G		intron	N/A	ENSP00000378537.4
	STRA6	ENST00000563965.5	TSL:1	c.1284-10C>G		intron	N/A	ENSP00000456609.1
	STRA6	ENST00000423167.6	TSL:1	c.1140-10C>G		intron	N/A	ENSP00000413012.2

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Matthew-Wood syndrome (2)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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;