15-74182504-T-G

Variant names:

• chr15-74182504-T-G
• rs351240
• NM_022369.4:c.1301-44A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_022369.4(STRA6):​c.1301-44A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0025 in 1,535,140 control chromosomes in the GnomAD database, including 68 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.012 (35 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (33 hom.)
• Consequence: STRA6 NM_022369.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.05
• Publications: 4 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 -12 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but rather VUS (scored 4 / 10). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0118 (1802/152266) while in subpopulation AFR AF = 0.0398 (1654/41540). AF 95% confidence interval is 0.0382. There are 35 homozygotes in GnomAd4. There are 867 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 35 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STRA6	NM_022369.4	MANE Select	c.1301-44A>C		intron	N/A	NP_071764.3
	STRA6	NM_001199042.2		c.1418-44A>C		intron	N/A	NP_001185971.1
	STRA6	NM_001199040.2		c.1412-44A>C		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.1301-44A>C		intron	N/A	ENSP00000378537.4
	STRA6	ENST00000563965.5	TSL:1	c.1418-44A>C		intron	N/A	ENSP00000456609.1
	STRA6	ENST00000423167.6	TSL:1	c.1274-44A>C		intron	N/A	ENSP00000413012.2

Frequencies

GnomAD3 genomes AF: 0.0118 AC: 1790 AN: 152150 Hom.: 35 Cov.: 32

Gnomad AFR AF: 0.0396

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00543

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.0138

GnomAD2 exomes AF: 0.00329 AC: 560 AN: 170358 AF XY: 0.00252

Gnomad AFR exome AF: 0.0439

Gnomad AMR exome AF: 0.00292

Gnomad ASJ exome AF: 0.00314

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000408

Gnomad OTH exome AF: 0.00282

GnomAD4 exome AF: 0.00148 AC: 2040 AN: 1382874 Hom.: 33 Cov.: 24 AF XY: 0.00141 AC XY: 968 AN XY: 685842

African (AFR) AF: 0.0394 AC: 1248 AN: 31640

American (AMR) AF: 0.00345 AC: 130 AN: 37708

Ashkenazi Jewish (ASJ) AF: 0.00275 AC: 69 AN: 25132

East Asian (EAS) AF: 0.00 AC: 0 AN: 36976

South Asian (SAS) AF: 0.000238 AC: 19 AN: 79968

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49392

Middle Eastern (MID) AF: 0.00580 AC: 25 AN: 4312

European-Non Finnish (NFE) AF: 0.000303 AC: 321 AN: 1060262

Other (OTH) AF: 0.00397 AC: 228 AN: 57484

GnomAD4 genome AF: 0.0118 AC: 1802 AN: 152266 Hom.: 35 Cov.: 32 AF XY: 0.0116 AC XY: 867 AN XY: 74458

African (AFR) AF: 0.0398 AC: 1654 AN: 41540

American (AMR) AF: 0.00542 AC: 83 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68012

Other (OTH) AF: 0.0137 AC: 29 AN: 2116

Alfa AF: 0.00641 Hom.: 0

Bravo AF: 0.0129

Asia WGS AF: 0.00520 AC: 19 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.19
DANN	Benign	0.41
PhyloP100		-1.1
La Branchor		0.94
BranchPoint Hunter		4.0
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs351240; hg19: chr15-74474845;