NM_002099.8:c.343C>T

Variant names:

• chr4-144116868-G-A
• rs572116498
• NM_002099.8:c.343C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002099.8(GYPA):​c.343C>T​(p.Arg115Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000101 in 1,588,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R115S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000077 (0 hom.)
• Consequence: GYPA NM_002099.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.76
• Publications: 7 publications found

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]

ENSG00000285783 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06257388).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002099.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GYPA	NM_002099.8	MANE Select	c.343C>T	p.Arg115Cys	missense	Exon 5 of 7	NP_002090.4	P02724-1
	GYPA	NM_001438046.1		c.343C>T	p.Arg115Cys	missense	Exon 5 of 6	NP_001424975.1	A0A2R8Y7F9
	GYPA	NM_001308187.2		c.304C>T	p.Arg102Cys	missense	Exon 4 of 6	NP_001295116.1	E9PD10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GYPA	ENST00000641688.3	MANE Select	c.343C>T	p.Arg115Cys	missense	Exon 5 of 7	ENSP00000493142.2	P02724-1
	GYPA	ENST00000360771.8	TSL:1	c.343C>T	p.Arg115Cys	missense	Exon 5 of 7	ENSP00000354003.4	P02724-1
	GYPA	ENST00000535709.6	TSL:1	c.337C>T	p.Arg113Cys	missense	Exon 6 of 8	ENSP00000445398.2	A0A087WU29

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152042 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 251000 AF XY: 0.0000147

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000766 AC: 11 AN: 1435860 Hom.: 0 Cov.: 27 AF XY: 0.00000977 AC XY: 7 AN XY: 716216

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32962

American (AMR) AF: 0.00 AC: 0 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25946

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39520

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 85762

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5712

European-Non Finnish (NFE) AF: 0.00000551 AC: 6 AN: 1088380

Other (OTH) AF: 0.0000336 AC: 2 AN: 59510

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000064835), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152160 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74400

African (AFR) AF: 0.0000482 AC: 2 AN: 41514

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.0000386 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.022
DANN	Benign	0.89
DEOGEN2	Benign	0.081	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.0029	N
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.063	T
MetaSVM	Benign	-0.58	T
PhyloP100		-4.8
PrimateAI	Benign	0.22	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.071
Sift	Benign	0.079	T
Sift4G	Benign	0.068	T
Polyphen		1.0	D
Vest4		0.21
MutPred		0.47		Loss of MoRF binding (P = 0.0079)
MVP		0.030
MPC		0.022
ClinPred		0.45	T
GERP RS		-9.6
gMVP		0.032
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs572116498; hg19: chr4-145038021; COSMIC: COSV51626818; COSMIC: COSV51626818;