Genetic Variant NM_002100.6:c.250A>G (chr4-143997560-T-C) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_002100.6(GYPB):c.250A>G(p.Ser84Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000605 in 1,589,484 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0017 ( 9 hom., cov: 32)

Exomes 𝑓: 0.00049 ( 10 hom. )

Consequence

GYPB
NM_002100.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -1.18

Publications

3 publications found

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:

GUSBP5 (HGNC:):

GUSBP5 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.006).

BP6

Variant 4-143997560-T-C is Benign according to our data. Variant chr4-143997560-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3388470.

BS2

High Homozygotes in GnomAd4 at 9 BG gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002100.6. 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
	GYPB	NM_002100.6	MANE Select	c.250A>G	p.Ser84Gly	missense	Exon 4 of 5	NP_002091.4	P06028-1
	GYPB	NM_001304382.1		c.172A>G	p.Ser58Gly	missense	Exon 5 of 6	NP_001291311.1	P06028

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GYPB	ENST00000502664.6	TSL:1 MANE Select	c.250A>G	p.Ser84Gly	missense	Exon 4 of 5	ENSP00000427690.1	P06028-1
GYPB	ENST00000506516.6	TSL:1	c.172A>G	p.Ser58Gly	missense	Exon 5 of 6	ENSP00000424025.2	D6RBP2
GYPB	ENST00000513128.5	TSL:1	c.151A>G	p.Ser51Gly	missense	Exon 3 of 4	ENSP00000425244.1	P06028-2

Frequencies

GnomAD3 genomes

AF:

0.00169

AC:

256

AN:

151246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00424

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00288

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000470

Gnomad OTH

AF:

0.00288

GnomAD2 exomes

AF:

0.000615

AC:

154

AN:

250396

AF XY:

0.000553

show subpopulations

Gnomad AFR exome

AF:

0.00419

Gnomad AMR exome

AF:

0.00119

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000371

Gnomad OTH exome

AF:

0.000329

GnomAD4 exome

AF:

0.000490

AC:

705

AN:

1438122

Hom.:

Cov.:

AF XY:

0.000482

AC XY:

346

AN XY:

717200

show subpopulations

African (AFR)

AF:

0.00341

AC:

109

AN:

31928

American (AMR)

AF:

0.00125

AC:

AN:

44640

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25956

East Asian (EAS)

AF:

0.0000507

AC:

AN:

39450

South Asian (SAS)

AF:

0.0000350

AC:

AN:

85684

European-Finnish (FIN)

AF:

0.0000375

AC:

AN:

53294

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

0.000451

AC:

493

AN:

1092012

Other (OTH)

AF:

0.000673

AC:

AN:

59462

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

123

154

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00169

AC:

256

AN:

151362

Hom.:

Cov.:

AF XY:

0.00143

AC XY:

106

AN XY:

74028

show subpopulations

African (AFR)

AF:

0.00423

AC:

172

AN:

40680

American (AMR)

AF:

0.00288

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000207

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0000943

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000471

AC:

AN:

68008

Other (OTH)

AF:

0.00285

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000959

Hom.:

Bravo

AF:

0.00213

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00616

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000610

AC:

Asia WGS

AF:

0.000578

AC:

AN:

3476

EpiCase

AF:

0.000327

EpiControl

AF:

0.000356

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.90

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.022

(source)

DANN

Benign

0.43

Eigen

Benign

-1.9

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.0034

M_CAP

Benign

0.00054

PhyloP100

-1.2

ClinPred

0.0032

GERP RS

-4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.042

Mutation Taster

=99/1

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over