4-143999413-G-C

Position:

chr4-143999413-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_002100.6(GYPB):c.173C>G(p.Pro58Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000481 in 1,517,026 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as association (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000047 ( 1 hom. )

Consequence

GYPB
NM_002100.6 missense, splice_region

Scores

Splicing: ADA: 0.00005388

Clinical Significance

association no assertion criteria provided O:1

Conservation

PhyloP100: 0.838

Variant links:

Genes affected

GYPB (HGNC:4703): (glycophorin B (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. GYPB gene consists of 5 exons and has 97% sequence homology with GYPA from the 5' UTR to the coding sequence encoding the first 45 amino acids. 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; also, 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. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jan 2015]

GYPB links:

GYPB (HGNC:):

GYPB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.018347174).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GYPB	NM_002100.6 linkuse as main transcript	c.173C>G	p.Pro58Arg	missense_variant, splice_region_variant	3/5	ENST00000502664.6	NP_002091.4	P06028-1
GYPB	NM_001304382.1 linkuse as main transcript	c.95C>G	p.Pro32Arg	missense_variant, splice_region_variant	4/6		NP_001291311.1	P06028
GYPB	XM_011531903.3 linkuse as main transcript	c.173C>G	p.Pro58Arg	missense_variant, splice_region_variant	3/5		XP_011530205.1
GYPB	XM_011531904.4 linkuse as main transcript	c.146C>G	p.Pro49Arg	missense_variant, splice_region_variant	4/6		XP_011530206.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
GYPB	ENST00000502664.6 linkuse as main transcript	c.173C>G	p.Pro58Arg	missense_variant, splice_region_variant	3/5	1	NM_002100.6	ENSP00000427690.1	P06028-1
GYPB	ENST00000504951.6 linkuse as main transcript	n.*252C>G		splice_region_variant, non_coding_transcript_exon_variant	5/7	1		ENSP00000421974.2	D6RA87
GYPB	ENST00000504951.6 linkuse as main transcript	n.*252C>G		3_prime_UTR_variant	5/7	1		ENSP00000421974.2	D6RA87

Frequencies

GnomAD3 genomes

AF:

0.0000661

AC:

AN:

151308

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00173

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000184

AC:

AN:

239312

Hom.:

AF XY:

0.000186

AC XY:

AN XY:

129330

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00214

Gnomad SAS exome

AF:

0.000140

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000342

GnomAD4 exome

AF:

0.0000469

AC:

AN:

1365602

Hom.:

Cov.:

AF XY:

0.0000541

AC XY:

AN XY:

683866

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000793

Gnomad4 SAS exome

AF:

0.000218

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000291

Gnomad4 OTH exome

AF:

0.000210

GnomAD4 genome

AF:

0.0000594

AC:

AN:

151424

Hom.:

Cov.:

AF XY:

0.0000540

AC XY:

AN XY:

74026

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00154

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000279

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.000124

AC:

Asia WGS

AF:

0.00318

AC:

AN:

3474

ClinVar

Significance: association

Submissions summary: Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

BLOOD GROUP, Ss

Other:1

association, no assertion criteria provided

research

Australian Red Cross Blood Service

Background: The GYPB c.173C>G leads to an amino acid change p.Pro58Arg (CCA>CGA) on GPB. GYPB c.173C>G is the molecular basis for the blood group antigen sD (MNS23) of the MNS blood group system. The sD is considered a low-frequency antigen detected in 1 in 1000 Caucasian South Africans and Mixed race South Africans. Antibody against sD have been reported to cause severe hemolytic disease of the fetus and newborn (HDFN). Current case: The GYPB c.173C>G was detected in a newborn child inherited from the father. This variant was not detected in the mother of the newborn child. All family members were of Thai ethnicity. The mother developed an antibody against the baby's red blood cells (RBC) and the antibody was also reactive with the father's RBC. No other RBC antibodies were detected in the mother's plasma using a cell panel. The baby was diagnosed with HDFN requiring blood transfusion and phototherapy. The affected newborn is the mother's second pregnancy. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.017

.;T;.;.;.

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.31

LIST_S2

Benign

0.23

T;T;T;T;T

M_CAP

Benign

0.0021

MetaRNN

Benign

0.016

T;T;T;T;T

MetaSVM

Benign

-1.1

PROVEAN

Pathogenic

-5.4

D;D;D;.;.

REVEL

Benign

0.098

Sift

Pathogenic

0.0

D;D;T;.;.

Sift4G

Pathogenic

0.0

D;D;D;.;.

Vest4

0.34

MutPred

0.61

Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);.;.;.;

MVP

0.095

MPC

0.0089

ClinPred

0.19

GERP RS

0.12

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.19

gMVP

0.040

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000054

dbscSNV1_RF

Benign

0.15

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