rs372651860

Variant names:

• chr14-74260772-T-A
• rs372651860
• NM_182894.3:c.939T>A

Your query was ambiguous. Multiple possible variants found:

• chr14-74260772-T-A
• chr14-74260772-T-G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS1

The NM_182894.3(VSX2):​c.939T>A​(p.Ala313Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000609 in 1,583,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A313A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00050 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00062 (0 hom.)
• Consequence: VSX2 NM_182894.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 0.363
• Publications: 0 publications found

Genes affected

VSX2 (HGNC:1975): (visual system homeobox 2) This gene encodes a homeobox protein originally described as a retina-specific transcription factor. Mutations in this gene are associated with microphthalmia, cataracts and iris abnormalities. [provided by RefSeq, Oct 2009]

VSX2 Gene-Disease associations (from GenCC):

• isolated microphthalmia 2

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• microphthalmia, isolated, with coloboma 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• microphthalmia

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics
• isolated anophthalmia-microphthalmia syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• microphthalmia, isolated, with coloboma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 14-74260772-T-A is Benign according to our data. Variant chr14-74260772-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 314203.
• BP7: Synonymous conserved (PhyloP=0.363 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0005 (76/152080) while in subpopulation NFE AF = 0.000633 (43/67958). AF 95% confidence interval is 0.000482. There are 0 homozygotes in GnomAd4. There are 40 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182894.3. 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
	VSX2	NM_182894.3	MANE Select	c.939T>A	p.Ala313Ala	synonymous	Exon 5 of 5	NP_878314.1	P58304

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VSX2	ENST00000261980.3	TSL:1 MANE Select	c.939T>A	p.Ala313Ala	synonymous	Exon 5 of 5	ENSP00000261980.2	P58304

Frequencies

GnomAD3 genomes AF: 0.000500 AC: 76 AN: 151962 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000633

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000600 AC: 118 AN: 196808 AF XY: 0.000491

Gnomad AFR exome AF: 0.000172

Gnomad AMR exome AF: 0.000140

Gnomad ASJ exome AF: 0.00512

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000579

Gnomad NFE exome AF: 0.000730

Gnomad OTH exome AF: 0.000586

GnomAD4 exome AF: 0.000620 AC: 888 AN: 1431682 Hom.: 0 Cov.: 31 AF XY: 0.000584 AC XY: 414 AN XY: 709174

African (AFR) AF: 0.000212 AC: 7 AN: 32992

American (AMR) AF: 0.000126 AC: 5 AN: 39738

Ashkenazi Jewish (ASJ) AF: 0.00451 AC: 115 AN: 25492

East Asian (EAS) AF: 0.00 AC: 0 AN: 38348

South Asian (SAS) AF: 0.00 AC: 0 AN: 81858

European-Finnish (FIN) AF: 0.0000980 AC: 5 AN: 51026

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5740

European-Non Finnish (NFE) AF: 0.000652 AC: 715 AN: 1097200

Other (OTH) AF: 0.000675 AC: 40 AN: 59288

GnomAD4 genome AF: 0.000500 AC: 76 AN: 152080 Hom.: 0 Cov.: 33 AF XY: 0.000538 AC XY: 40 AN XY: 74328

African (AFR) AF: 0.000145 AC: 6 AN: 41514

American (AMR) AF: 0.000131 AC: 2 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5142

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10580

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

European-Non Finnish (NFE) AF: 0.000633 AC: 43 AN: 67958

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.00108 Hom.: 0

Bravo AF: 0.000389

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Isolated microphthalmia 2 (2)
-	-	1	Microphthalmia (1)
-	1	-	Microphthalmia, isolated, with coloboma 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	8.3
DANN	Benign	0.69
PhyloP100		0.36
Mutation Taster		=97/3	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: rs372651860; hg19: chr14-74727475; COSMIC: COSV56217340;