Genetic Variant GYPB:p.Thr48Lys (chr4-143999443-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

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

The NM_002100.6(GYPB):c.143C>A(p.Thr48Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000199 in 1,507,928 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T48M) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 7.4e-7 ( 0 hom. )

Consequence

GYPB
NM_002100.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -4.15

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:

ENSG00000251600 (HGNC:):

ENSG00000251600 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=0.034067392).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GYPB	NM_002100.6 link	c.143C>A	p.Thr48Lys	missense_variant	Exon 3 of 5	ENST00000502664.6	NP_002091.4	P06028-1
GYPB	NM_001304382.1 link	c.65C>A	p.Thr22Lys	missense_variant	Exon 4 of 6		NP_001291311.1	P06028
GYPB	XM_011531903.3 link	c.143C>A	p.Thr48Lys	missense_variant	Exon 3 of 5		XP_011530205.1
GYPB	XM_011531904.4 link	c.116C>A	p.Thr39Lys	missense_variant	Exon 4 of 6		XP_011530206.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GYPB	ENST00000502664.6 link	c.143C>A	p.Thr48Lys	missense_variant	Exon 3 of 5	1	NM_002100.6	ENSP00000427690.1	P06028-1
GYPB	ENST00000504951.6 link	n.*222C>A		non_coding_transcript_exon_variant	Exon 5 of 7	1		ENSP00000421974.2	D6RA87
GYPB	ENST00000504951.6 link	n.*222C>A		3_prime_UTR_variant	Exon 5 of 7	1		ENSP00000421974.2	D6RA87

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

7.37e-7

AC:

AN:

1356814

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

679438

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.78e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151114

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73792

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.038

DANN

Benign

0.36

DEOGEN2

Benign

0.0059

.;T;.;.;.

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.0014

LIST_S2

Benign

0.26

T;T;T;T;T

M_CAP

Benign

0.0010

MetaRNN

Benign

0.034

T;T;T;T;T

MetaSVM

Benign

-0.97

PROVEAN

Benign

-1.9

N;N;N;.;.

REVEL

Benign

0.020

Sift

Benign

1.0

T;T;T;.;.

Sift4G

Benign

0.39

T;T;T;.;.

Vest4

0.089

MutPred

0.36

Gain of ubiquitination at T48 (P = 0.0101);Gain of ubiquitination at T48 (P = 0.0101);.;.;.;

MVP

0.014

MPC

0.0051

ClinPred

0.034

GERP RS

-3.3

Varity_R

0.033

gMVP

0.033

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

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over