14-74245180-C-T

Position:

• chr14-74245180-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_182894.3(VSX2):​c.471C>T​(p.Ser157Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.475 in 1,612,744 control chromosomes in the GnomAD database, including 194,901 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (13854 hom., cov: 27)
  • Exomes 𝑓: 0.49 (181047 hom.)
• Consequence: VSX2 NM_182894.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.399

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 14-74245180-C-T is Benign according to our data. Variant chr14-74245180-C-T is described in ClinVar as [Benign]. Clinvar id is 167840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-74245180-C-T is described in Lovd as [Benign]. Variant chr14-74245180-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.516 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VSX2	NM_182894.3	c.471C>T	p.Ser157Ser	synonymous_variant	3/5	ENST00000261980.3	NP_878314.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VSX2	ENST00000261980.3	c.471C>T	p.Ser157Ser	synonymous_variant	3/5	1	NM_182894.3	ENSP00000261980.2

Frequencies

GnomAD3 genomes AF: 0.382 AC: 57787 AN: 151214 Hom.: 13850 Cov.: 27

Gnomad AFR AF: 0.117

Gnomad AMI AF: 0.657

Gnomad AMR AF: 0.454

Gnomad ASJ AF: 0.387

Gnomad EAS AF: 0.0692

Gnomad SAS AF: 0.318

Gnomad FIN AF: 0.587

Gnomad MID AF: 0.296

Gnomad NFE AF: 0.521

Gnomad OTH AF: 0.370

GnomAD3 exomes AF: 0.429 AC: 107675 AN: 250814 Hom.: 26290 AF XY: 0.431 AC XY: 58428 AN XY: 135568

Gnomad AFR exome AF: 0.113

Gnomad AMR exome AF: 0.502

Gnomad ASJ exome AF: 0.392

Gnomad EAS exome AF: 0.0530

Gnomad SAS exome AF: 0.338

Gnomad FIN exome AF: 0.578

Gnomad NFE exome AF: 0.512

Gnomad OTH exome AF: 0.442

GnomAD4 exome AF: 0.485 AC: 708830 AN: 1461412 Hom.: 181047 Cov.: 53 AF XY: 0.482 AC XY: 350037 AN XY: 726970

Gnomad4 AFR exome AF: 0.0986

Gnomad4 AMR exome AF: 0.496

Gnomad4 ASJ exome AF: 0.392

Gnomad4 EAS exome AF: 0.0879

Gnomad4 SAS exome AF: 0.344

Gnomad4 FIN exome AF: 0.570

Gnomad4 NFE exome AF: 0.523

Gnomad4 OTH exome AF: 0.443

GnomAD4 genome AF: 0.382 AC: 57803 AN: 151332 Hom.: 13854 Cov.: 27 AF XY: 0.385 AC XY: 28473 AN XY: 73872

Gnomad4 AFR AF: 0.117

Gnomad4 AMR AF: 0.454

Gnomad4 ASJ AF: 0.387

Gnomad4 EAS AF: 0.0694

Gnomad4 SAS AF: 0.317

Gnomad4 FIN AF: 0.587

Gnomad4 NFE AF: 0.521

Gnomad4 OTH AF: 0.371

Alfa AF: 0.459 Hom.: 8796

Bravo AF: 0.360

Asia WGS AF: 0.219 AC: 761 AN: 3478

EpiCase AF: 0.495

EpiControl AF: 0.497

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 27, 2014	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Isolated microphthalmia 2 Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Microphthalmia, isolated, with coloboma 3 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Microphthalmia Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 19, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
CADD	Benign	18
DANN	Benign	0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.41		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.41		Position offset: 7

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs35435463; hg19: chr14-74711883; COSMIC: COSV56216854;