chr4-144120554-C-A

Variant names:

• chr4-144120554-C-A
• rs7658293
• NM_002099.8:c.72G>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_002099.8(GYPA):​c.72G>T​(p.Glu24Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.226 in 999,138 control chromosomes in the GnomAD database, including 74,231 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.45 (11689 hom., cov: 19)
  • Exomes 𝑓: 0.20 (62542 hom.)
• Consequence: GYPA NM_002099.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.682
• Publications: 14 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.982088E-4).
• BS2: High Homozygotes in GnomAd4 at 11689 BG gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GYPA	NM_002099.8	MANE Select	c.72G>T	p.Glu24Asp	missense	Exon 2 of 7	NP_002090.4
	GYPA	NM_001438627.1		c.-7G>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 8	NP_001425556.1
	GYPA	NM_001438046.1		c.72G>T	p.Glu24Asp	missense	Exon 2 of 6	NP_001424975.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GYPA	ENST00000641688.3	MANE Select	c.72G>T	p.Glu24Asp	missense	Exon 2 of 7	ENSP00000493142.2
	GYPA	ENST00000360771.8	TSL:1	c.72G>T	p.Glu24Asp	missense	Exon 2 of 7	ENSP00000354003.4
	GYPA	ENST00000535709.6	TSL:1	c.66G>T	p.Glu22Asp	missense	Exon 3 of 8	ENSP00000445398.2

Frequencies

GnomAD3 genomes AF: 0.451 AC: 47020 AN: 104240 Hom.: 11673 Cov.: 19

Gnomad AFR AF: 0.381

Gnomad AMI AF: 0.404

Gnomad AMR AF: 0.481

Gnomad ASJ AF: 0.489

Gnomad EAS AF: 0.441

Gnomad SAS AF: 0.472

Gnomad FIN AF: 0.533

Gnomad MID AF: 0.525

Gnomad NFE AF: 0.475

Gnomad OTH AF: 0.409

GnomAD2 exomes AF: 0.129 AC: 20346 AN: 157362 AF XY: 0.119

Gnomad AFR exome AF: 0.134

Gnomad AMR exome AF: 0.240

Gnomad ASJ exome AF: 0.0861

Gnomad EAS exome AF: 0.241

Gnomad FIN exome AF: 0.0493

Gnomad NFE exome AF: 0.0934

Gnomad OTH exome AF: 0.188

GnomAD4 exome AF: 0.200 AC: 178520 AN: 894792 Hom.: 62542 Cov.: 29 AF XY: 0.211 AC XY: 94518 AN XY: 446930

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

African (AFR) AF: 0.174 AC: 4078 AN: 23478

American (AMR) AF: 0.339 AC: 8988 AN: 26478

Ashkenazi Jewish (ASJ) AF: 0.301 AC: 4979 AN: 16534

East Asian (EAS) AF: 0.425 AC: 11041 AN: 25956

South Asian (SAS) AF: 0.431 AC: 24589 AN: 57052

European-Finnish (FIN) AF: 0.468 AC: 15121 AN: 32332

Middle Eastern (MID) AF: 0.229 AC: 770 AN: 3356

European-Non Finnish (NFE) AF: 0.148 AC: 99329 AN: 672496

Other (OTH) AF: 0.259 AC: 9625 AN: 37110

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.451 AC: 47062 AN: 104346 Hom.: 11689 Cov.: 19 AF XY: 0.451 AC XY: 22417 AN XY: 49752

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

African (AFR) AF: 0.381 AC: 10954 AN: 28764

American (AMR) AF: 0.482 AC: 4797 AN: 9954

Ashkenazi Jewish (ASJ) AF: 0.489 AC: 1221 AN: 2498

East Asian (EAS) AF: 0.441 AC: 1502 AN: 3408

South Asian (SAS) AF: 0.474 AC: 1257 AN: 2652

European-Finnish (FIN) AF: 0.533 AC: 3399 AN: 6374

Middle Eastern (MID) AF: 0.533 AC: 113 AN: 212

European-Non Finnish (NFE) AF: 0.475 AC: 22969 AN: 48380

Other (OTH) AF: 0.404 AC: 575 AN: 1424

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.534 Hom.: 2784

ExAC AF: 0.0194 AC: 1695

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.77
DANN	Benign	0.42
DEOGEN2	Benign	0.023	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.00093	N
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.00070	T
MetaSVM	Benign	-0.95	T
PhyloP100		0.68
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.83	N
REVEL	Benign	0.026
Sift	Benign	0.45	T
Sift4G	Benign	0.64	T
Polyphen		0.61	P
Vest4		0.053
MutPred		0.31		Loss of glycosylation at T23 (P = 0.0157)
MPC		0.040
ClinPred		0.0073	T
GERP RS		-1.8
gMVP		0.018
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7658293; hg19: chr4-145041707; COSMIC: COSV51629959; COSMIC: COSV51629959;