chr4-144116874-C-T

Variant names:

• chr4-144116874-C-T
• rs146754148
• NM_002099.8:c.337G>A

Variant summary

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

The NM_002099.8(GYPA):​c.337G>A​(p.Gly113Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000813 in 1,594,830 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00089 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00080 (7 hom.)
• Consequence: GYPA NM_002099.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.12
• Publications: 4 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=0.005676508).
• BS2: High Homozygotes in GnomAdExome4 at 7 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GYPA	NM_002099.8	MANE Select	c.337G>A	p.Gly113Ser	missense	Exon 5 of 7	NP_002090.4	P02724-1
	GYPA	NM_001438046.1		c.337G>A	p.Gly113Ser	missense	Exon 5 of 6	NP_001424975.1	A0A2R8Y7F9
	GYPA	NM_001308187.2		c.298G>A	p.Gly100Ser	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.337G>A	p.Gly113Ser	missense	Exon 5 of 7	ENSP00000493142.2	P02724-1
	GYPA	ENST00000360771.8	TSL:1	c.337G>A	p.Gly113Ser	missense	Exon 5 of 7	ENSP00000354003.4	P02724-1
	GYPA	ENST00000535709.6	TSL:1	c.331G>A	p.Gly111Ser	missense	Exon 6 of 8	ENSP00000445398.2	A0A087WU29

Frequencies

GnomAD3 genomes AF: 0.000889 AC: 135 AN: 151934 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000194

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00125

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00119 AC: 299 AN: 251010 AF XY: 0.00121

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00165

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00117

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.000805 AC: 1161 AN: 1442780 Hom.: 7 Cov.: 27 AF XY: 0.000880 AC XY: 633 AN XY: 719190

African (AFR) AF: 0.000121 AC: 4 AN: 33146

American (AMR) AF: 0.00161 AC: 72 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.00146 AC: 38 AN: 25998

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39544

South Asian (SAS) AF: 0.00248 AC: 213 AN: 85898

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53398

Middle Eastern (MID) AF: 0.00628 AC: 36 AN: 5734

European-Non Finnish (NFE) AF: 0.000659 AC: 721 AN: 1094662

Other (OTH) AF: 0.00122 AC: 73 AN: 59718

GnomAD4 genome AF: 0.000888 AC: 135 AN: 152050 Hom.: 0 Cov.: 33 AF XY: 0.000996 AC XY: 74 AN XY: 74310

African (AFR) AF: 0.000193 AC: 8 AN: 41454

American (AMR) AF: 0.00177 AC: 27 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10554

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00125 AC: 85 AN: 67988

Other (OTH) AF: 0.00142 AC: 3 AN: 2108

Alfa AF: 0.000930 Hom.: 0

Bravo AF: 0.000903

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.00113 AC: 137

EpiCase AF: 0.00175

EpiControl AF: 0.00213

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.022
DANN	Benign	0.68
DEOGEN2	Benign	0.0027	T
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.0086	N
LIST_S2	Benign	0.14	T
M_CAP	Benign	0.0023	T
MetaRNN	Benign	0.0057	T
MetaSVM	Benign	-1.0	T
PhyloP100		-1.1
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.95	N
REVEL	Benign	0.025
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.033	B
Vest4		0.16
MVP		0.030
MPC		0.020
ClinPred		0.0063	T
GERP RS		-9.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.022
Mutation Taster		=98/2	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: rs146754148; hg19: chr4-145038027; COSMIC: COSV51623734; COSMIC: COSV51623734;