chr4-144116906-C-T

Position:

chr4-144116906-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP3

The NM_002099.8(GYPA):c.305G>A(p.Gly102Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000107 in 1,595,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

GYPA
NM_002099.8 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.16

Variant links:

Genes affected

GYPA (HGNC:4702): (glycophorin A (MNS blood group)) Glycophorins A (GYPA) and B (GYPB) are major sialoglycoproteins of the human erythrocyte membrane which bear the antigenic determinants for the MN and Ss blood groups. In addition to the M or N and S or s antigens that commonly occur in all populations, about 40 related variant phenotypes have been identified. These variants include all the variants of the Miltenberger complex and several isoforms of Sta, as well as Dantu, Sat, He, Mg, and deletion variants Ena, S-s-U- and Mk. Most of the variants are the result of gene recombinations between GYPA and GYPB. [provided by RefSeq, Jul 2008]

GYPA links:

LOC105377460 (HGNC:):

LOC105377460 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM1

In a mutagenesis_site Abolishes dimerization. (size 0) in uniprot entity GLPA_HUMAN

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.827

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GYPA	NM_002099.8 linkuse as main transcript	c.305G>A	p.Gly102Asp	missense_variant	5/7	ENST00000641688.3	NP_002090.4
LOC105377460	XR_002959803.2 linkuse as main transcript	n.5270+1677C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GYPA	ENST00000641688.3 linkuse as main transcript	c.305G>A	p.Gly102Asp	missense_variant	5/7		NM_002099.8	ENSP00000493142	P4

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000438

AC:

AN:

250936

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135590

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000272

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000353

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000104

AC:

AN:

1443426

Hom.:

Cov.:

AF XY:

0.00000834

AC XY:

AN XY:

719500

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000448

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000822

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152244

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.00000756

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000577

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 19, 2024

The c.305G>A (p.G102D) alteration is located in exon 5 (coding exon 5) of the GYPA gene. This alteration results from a G to A substitution at nucleotide position 305, causing the glycine (G) at amino acid position 102 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.26

CADD

Benign

9.1

DANN

Benign

0.97

DEOGEN2

Benign

0.17

.;T;T;.;.;.;.;.;.;T;T;.;.;.

Eigen

Benign

-0.73

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.021

LIST_S2

Benign

0.59

T;.;T;T;T;.;.;T;T;T;T;T;T;T

M_CAP

Benign

0.024

MetaRNN

Pathogenic

0.83

D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.78

MutationTaster

Benign

1.0

N;N;N;N;N;N;N;N

PrimateAI

Benign

0.33

PROVEAN

Pathogenic

-4.6

.;.;D;.;D;.;.;.;.;.;D;D;D;D

REVEL

Benign

0.28

Sift

Uncertain

0.0020

.;.;D;.;D;.;.;.;.;.;D;D;D;D

Sift4G

Uncertain

0.038

D;.;T;.;D;.;D;.;.;.;T;D;D;D

Polyphen

1.0, 1.0

.;.;.;.;.;.;.;.;.;.;D;D;D;.

Vest4

0.61

MutPred

0.88

.;Loss of stability (P = 0.2124);Loss of stability (P = 0.2124);Loss of stability (P = 0.2124);.;.;.;.;.;.;.;.;.;.;

MVP

0.48

MPC

0.17

ClinPred

0.85

GERP RS

-3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.13

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