4-144001187-T-C

Position:

• chr4-144001187-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002100.6(GYPB):​c.134A>G​(p.Asn45Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GYPB NM_002100.6 missense, splice_region
• Scores: Splicing: ADA: 0.001118
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.43

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12440029).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GYPB	NM_002100.6	c.134A>G	p.Asn45Ser	missense_variant, splice_region_variant	2/5	ENST00000502664.6	NP_002091.4
GYPB	NM_001304382.1	c.56A>G	p.Asn19Ser	missense_variant, splice_region_variant	3/6		NP_001291311.1
GYPB	XM_011531903.3	c.134A>G	p.Asn45Ser	missense_variant, splice_region_variant	2/5		XP_011530205.1
GYPB	XM_011531904.4	c.107A>G	p.Asn36Ser	missense_variant, splice_region_variant	3/6		XP_011530206.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GYPB	ENST00000502664.6	c.134A>G	p.Asn45Ser	missense_variant, splice_region_variant	2/5	1	NM_002100.6	ENSP00000427690.1
GYPB	ENST00000504951.6	n.*120A>G		splice_region_variant, non_coding_transcript_exon_variant	3/7	1		ENSP00000421974.2
GYPB	ENST00000504951.6	n.*120A>G		3_prime_UTR_variant	3/7	1		ENSP00000421974.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2024

The c.134A>G (p.N45S) alteration is located in exon 2 (coding exon 2) of the GYPB gene. This alteration results from a A to G substitution at nucleotide position 134, causing the asparagine (N) at amino acid position 45 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.0030
DANN	Benign	0.64
DEOGEN2	Benign	0.0070	.;T;.;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0016	N
LIST_S2	Benign	0.49	T;T;T;T
M_CAP	Benign	0.00059	T
MetaRNN	Benign	0.12	T;T;T;T
MetaSVM	Benign	-1.1	T
PROVEAN	Pathogenic	-4.7	D;D;.;.
REVEL	Benign	0.020
Sift	Pathogenic	0.0	D;D;.;.
Sift4G	Uncertain	0.034	D;T;.;.
Vest4		0.11
MutPred		0.46		Gain of disorder (P = 0.0769);Gain of disorder (P = 0.0769);.;Gain of disorder (P = 0.0769);
MVP		0.030
MPC		0.0061
ClinPred		0.11	T
GERP RS		-3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.058
gMVP		0.016

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0011
dbscSNV1_RF	Benign	0.082
SpliceAI score (max)		0.43		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.43		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-144922340;