4-144120558-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.722

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]

LOC105377460 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06538156).
• BS2: High Homozygotes in GnomAdExome at 6 BG gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GYPA	NM_002099.8	c.68C>A	p.Thr23Asn	missense_variant	2/7	ENST00000641688.3
LOC105377460	XR_002959803.2	n.5270+5329G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GYPA	ENST00000641688.3	c.68C>A	p.Thr23Asn	missense_variant	2/7		NM_002099.8	P4

Frequencies

GnomAD3 genomes AF: 0.0000613 AC: 8 AN: 130534 Hom.: 0 Cov.: 20

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: 20 AN: 180324 Hom.: 6 AF XY: 0.000134 AC XY: 13 AN XY: 96832

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: 30 AN: 1114428 Hom.: 2 Cov.: 29 AF XY: 0.0000269 AC XY: 15 AN XY: 557994

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: 8 AN: 130534 Hom.: 0 Cov.: 20 AF XY: 0.0000796 AC XY: 5 AN XY: 62794

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.: 1

ExAC AF: 0.000106 AC: 10

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	11
Dann	Benign	0.97
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.85	D;.;D;D;.;D;T;T
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.065	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.26	T
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	D
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

Other links and lift over

dbSNP: rs753693249; hg19: chr4-145041711; COSMIC: COSV51632823; COSMIC: COSV51632823;