chr14-74260704-G-A

Variant names:

• chr14-74260704-G-A
• rs75395981
• NM_182894.3:c.871G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_182894.3(VSX2):​c.871G>A​(p.Asp291Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0132 in 1,593,940 control chromosomes in the GnomAD database, including 542 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. D291D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.017 (82 hom., cov: 33)
  • Exomes 𝑓: 0.013 (460 hom.)
• Consequence: VSX2 NM_182894.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 6.91
• Publications: 15 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015234649).
• BP6: Variant 14-74260704-G-A is Benign according to our data. Variant chr14-74260704-G-A is described in ClinVar as Benign. ClinVar VariationId is 197895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0824 is higher than 0.05.

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.871G>A	p.Asp291Asn	missense	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.871G>A	p.Asp291Asn	missense	Exon 5 of 5	ENSP00000261980.2	P58304

Frequencies

GnomAD3 genomes AF: 0.0172 AC: 2617 AN: 152214 Hom.: 81 Cov.: 33

Gnomad AFR AF: 0.00654

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0861

Gnomad ASJ AF: 0.0213

Gnomad EAS AF: 0.0276

Gnomad SAS AF: 0.0331

Gnomad FIN AF: 0.00574

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00810

Gnomad OTH AF: 0.0191

GnomAD2 exomes AF: 0.0303 AC: 6417 AN: 211694 AF XY: 0.0263

Gnomad AFR exome AF: 0.00642

Gnomad AMR exome AF: 0.128

Gnomad ASJ exome AF: 0.0228

Gnomad EAS exome AF: 0.0274

Gnomad FIN exome AF: 0.00651

Gnomad NFE exome AF: 0.00882

Gnomad OTH exome AF: 0.0227

GnomAD4 exome AF: 0.0128 AC: 18381 AN: 1441608 Hom.: 460 Cov.: 31 AF XY: 0.0126 AC XY: 9021 AN XY: 714970

African (AFR) AF: 0.00554 AC: 184 AN: 33242

American (AMR) AF: 0.120 AC: 4935 AN: 41176

Ashkenazi Jewish (ASJ) AF: 0.0243 AC: 622 AN: 25642

East Asian (EAS) AF: 0.0237 AC: 923 AN: 38956

South Asian (SAS) AF: 0.0259 AC: 2147 AN: 82978

European-Finnish (FIN) AF: 0.00641 AC: 330 AN: 51452

Middle Eastern (MID) AF: 0.0148 AC: 85 AN: 5750

European-Non Finnish (NFE) AF: 0.00747 AC: 8238 AN: 1102790

Other (OTH) AF: 0.0154 AC: 917 AN: 59622

GnomAD4 genome AF: 0.0173 AC: 2635 AN: 152332 Hom.: 82 Cov.: 33 AF XY: 0.0189 AC XY: 1406 AN XY: 74490

African (AFR) AF: 0.00678 AC: 282 AN: 41586

American (AMR) AF: 0.0863 AC: 1320 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0213 AC: 74 AN: 3470

East Asian (EAS) AF: 0.0276 AC: 143 AN: 5174

South Asian (SAS) AF: 0.0335 AC: 162 AN: 4832

European-Finnish (FIN) AF: 0.00574 AC: 61 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00810 AC: 551 AN: 68022

Other (OTH) AF: 0.0194 AC: 41 AN: 2116

Alfa AF: 0.0129 Hom.: 102

Bravo AF: 0.0233

TwinsUK AF: 0.00620 AC: 23

ALSPAC AF: 0.0112 AC: 43

ESP6500AA AF: 0.00525 AC: 23

ESP6500EA AF: 0.0107 AC: 92

ExAC AF: 0.0221 AC: 2677

Asia WGS AF: 0.0420 AC: 145 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Isolated microphthalmia 2 (3)
-	-	2	Microphthalmia, isolated, with coloboma 3 (2)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T
Eigen	Benign	-0.065
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	1.2	L
PhyloP100		6.9
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.26
Sift	Benign	0.035	D
Sift4G	Benign	0.24	T
Polyphen		0.13	B
Vest4		0.090
MPC		0.21
ClinPred		0.015	T
GERP RS		4.8
Varity_R		0.11
gMVP		0.21
Mutation Taster		=96/4	polymorphism (auto)

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: rs75395981; hg19: chr14-74727407; COSMIC: COSV100001544;