chr4-144120558-G-T

Position:

chr4-144120558-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_002099.8(GYPA):c.68C>A(p.Thr23Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000305 in 1,244,962 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.000061 ( 0 hom., cov: 20)

Exomes 𝑓: 0.000027 ( 2 hom. )

Consequence

GYPA
NM_002099.8 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.722

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 Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06538156).

BS2

High Homozygotes in GnomAdExome4 at 2 BG gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GYPA	NM_002099.8 linkuse as main transcript	c.68C>A	p.Thr23Asn	missense_variant	2/7	ENST00000641688.3	NP_002090.4
LOC105377460	XR_002959803.2 linkuse as main transcript	n.5270+5329G>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.68C>A	p.Thr23Asn	missense_variant	2/7		NM_002099.8	ENSP00000493142	P4

Frequencies

GnomAD3 genomes

AF:

0.0000613

AC:

AN:

130534

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000805

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000588

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000499

Gnomad OTH

AF:

0.00112

GnomAD3 exomes

AF:

0.000111

AC:

AN:

180324

Hom.:

AF XY:

0.000134

AC XY:

AN XY:

96832

show subpopulations

Gnomad AFR exome

AF:

0.000149

Gnomad AMR exome

AF:

0.0000862

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000198

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000131

Gnomad OTH exome

AF:

0.000220

GnomAD4 exome

AF:

0.0000269

AC:

AN:

1114428

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

557994

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000624

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000101

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000215

Gnomad4 OTH exome

AF:

0.0000425

GnomAD4 genome

AF:

0.0000613

AC:

AN:

130534

Hom.:

Cov.:

AF XY:

0.0000796

AC XY:

AN XY:

62794

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000805

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000588

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000499

Gnomad4 OTH

AF:

0.00112

Alfa

AF:

0.000194

Hom.:

ExAC

AF:

0.000106

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

Oct 20, 2021

The c.68C>A (p.T23N) alteration is located in exon 2 (coding exon 2) of the GYPA gene. This alteration results from a C to A substitution at nucleotide position 68, causing the threonine (T) at amino acid position 23 to be replaced by an asparagine (N). 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

Benign

0.19

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.13

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

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.85

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

M_CAP

Benign

0.0027

MetaRNN

Benign

0.065

T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

1.0

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

PrimateAI

Benign

0.26

PROVEAN

Uncertain

-2.7

.;.;D;.;N;N;N;D

REVEL

Benign

0.071

Sift

Uncertain

0.0020

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

Sift4G

Uncertain

0.022

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

Polyphen

0.99, 0.90

.;.;.;.;.;D;P;.

Vest4

0.20

MutPred

0.25

.;Loss of glycosylation at T23 (P = 0.017);Loss of glycosylation at T23 (P = 0.017);Loss of glycosylation at T23 (P = 0.017);.;Loss of glycosylation at T23 (P = 0.017);Loss of glycosylation at T23 (P = 0.017);Loss of glycosylation at T23 (P = 0.017);

MVP

0.19

MPC

0.17

ClinPred

0.62

GERP RS

1.7

gMVP

0.028

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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