Genetic Variant GYPA:p.Ser138Asn (chr4-144114712-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_002099.8(GYPA):c.413G>A(p.Ser138Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000481 in 1,454,290 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

GYPA
NM_002099.8 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.534

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:

ENSG00000285783 (HGNC:):

ENSG00000285783 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a modified_residue Phosphoserine (size 0) in uniprot entity GLPA_HUMAN

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09629372).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GYPA	NM_002099.8 link	c.413G>A	p.Ser138Asn	missense_variant	Exon 6 of 7	ENST00000641688.3	NP_002090.4	P02724A0A0C4DFT7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GYPA	ENST00000641688.3 link	c.413G>A	p.Ser138Asn	missense_variant	Exon 6 of 7		NM_002099.8	ENSP00000493142.2		A0A0C4DFT7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

250792

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135568

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:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000481

AC:

AN:

1454290

Hom.:

Cov.:

AF XY:

0.00000552

AC XY:

AN XY:

724052

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:

0.0000697

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3476

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.413G>A (p.S138N) alteration is located in exon 6 (coding exon 6) of the GYPA gene. This alteration results from a G to A substitution at nucleotide position 413, causing the serine (S) at amino acid position 138 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

Uncertain

0.54

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.63

CADD

Benign

5.9

DANN

Benign

0.97

DEOGEN2

Benign

0.020

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

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.017

LIST_S2

Benign

0.61

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

M_CAP

Benign

0.0089

MetaRNN

Benign

0.096

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

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.0

.;.;N;N;.;.;.;.;N;N;N;N

REVEL

Benign

0.024

Sift

Uncertain

0.0040

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

Sift4G

Pathogenic

0.0

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

Polyphen

0.26, 0.11, 0.45

.;.;.;.;.;.;.;.;B;B;B;.

Vest4

0.16

MutPred

0.37

.;Loss of phosphorylation at S138 (P = 0.0205);Loss of phosphorylation at S138 (P = 0.0205);.;.;.;.;.;.;.;.;.;

MVP

0.072

MPC

0.14

ClinPred

0.15

GERP RS

-1.5

gMVP

0.018

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