Variant chr14-94768983-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_173849.3(GSC):c.590T>C(p.Val197Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000555 in 1,440,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000056 ( 0 hom. )

Consequence

GSC
NM_173849.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.31

Variant links:

Genes affected

GSC (HGNC:4612): (goosecoid homeobox) This gene encodes a member of the bicoid subfamily of the paired (PRD) homeobox family of proteins. The encoded protein acts as a transcription factor and may be autoregulatory. A similar protein in mice plays a role in craniofacial and rib cage development during embryogenesis. [provided by RefSeq, Jul 2008]

GSC links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.853

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GSC	NM_173849.3 linkuse as main transcript	c.590T>C	p.Val197Ala	missense_variant	2/3	ENST00000238558.5	NP_776248.1	P56915

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GSC	ENST00000238558.5 linkuse as main transcript	c.590T>C	p.Val197Ala	missense_variant	2/3	1	NM_173849.3	ENSP00000238558.3		P56915

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000485

AC:

AN:

206348

Hom.:

AF XY:

0.00

AC XY:

AN XY:

112764

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000113

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000555

AC:

AN:

1440860

Hom.:

Cov.:

AF XY:

0.00000280

AC XY:

AN XY:

714918

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000725

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 23, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This variant has not been reported in the literature in individuals affected with GSC-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 197 of the GSC protein (p.Val197Ala). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.93

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.86

M_CAP

Pathogenic

0.45

MetaRNN

Pathogenic

0.85

MetaSVM

Pathogenic

0.93

MutationAssessor

Benign

1.4

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-3.6

REVEL

Pathogenic

0.82

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.0060

Polyphen

1.0

Vest4

0.77

MutPred

0.41

Loss of methylation at K196 (P = 0.0417);

MVP

0.99

MPC

2.4

ClinPred

0.96

GERP RS

4.2

Varity_R

0.57

gMVP

0.72

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over