rs753594601

Positions:

chr5-177608540-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_007255.3(B4GALT7):c.641G>A(p.Cys214Tyr) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000502 in 1,613,374 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

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

Exomes 𝑓: 0.000054 ( 0 hom. )

Consequence

B4GALT7
NM_007255.3 missense, splice_region

Scores

Splicing: ADA: 0.9442

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 9.46

Variant links:

Genes affected

B4GALT7 (HGNC:930): (beta-1,4-galactosyltransferase 7) This gene is a member of the beta-1,4-galactosyltransferase (beta4GalT) family. Family members encode type II membrane-bound glycoproteins that appear to have exclusive specificity for the donor substrate UDP-galactose. Each beta4GalT member has a distinct function in the biosynthesis of different glycoconjugates and saccharide structures. As type II membrane proteins, they have an N-terminal hydrophobic signal sequence that directs the protein to the Golgi apparatus which then remains uncleaved to function as a transmembrane anchor. The enzyme encoded by this gene attaches the first galactose in the common carbohydrate-protein linkage (GlcA-beta1,3-Gal-beta1,3-Gal-beta1,4-Xyl-beta1-O-Ser) found in proteoglycans. This enzyme differs from other beta4GalTs because it lacks the conserved Cys residues found in beta4GalT1-beta4GalT6 and it is located in cis-Golgi instead of trans-Golgi. Mutations in this gene have been associated with the progeroid form of Ehlers-Danlos syndrome. [provided by RefSeq, Oct 2009]

B4GALT7 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.914

PP5

Variant 5-177608540-G-A is Pathogenic according to our data. Variant chr5-177608540-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 253110.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}. Variant chr5-177608540-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
B4GALT7	NM_007255.3 linkuse as main transcript	c.641G>A	p.Cys214Tyr	missense_variant, splice_region_variant	4/6	ENST00000029410.10	NP_009186.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
B4GALT7	ENST00000029410.10 linkuse as main transcript	c.641G>A	p.Cys214Tyr	missense_variant, splice_region_variant	4/6	1	NM_007255.3	ENSP00000029410	P1
B4GALT7	ENST00000505145.1 linkuse as main transcript	n.1739G>A		splice_region_variant, non_coding_transcript_exon_variant	2/4	2
B4GALT7	ENST00000515353.1 linkuse as main transcript	n.1176G>A		non_coding_transcript_exon_variant	1/2	2
B4GALT7	ENST00000505433.5 linkuse as main transcript	c.*147G>A		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	4/6	5		ENSP00000425591

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152062

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000319

AC:

AN:

250770

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135716

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000706

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000541

AC:

AN:

1461312

Hom.:

Cov.:

AF XY:

0.0000660

AC XY:

AN XY:

727004

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:

0.0000711

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152062

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74288

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Ehlers-Danlos syndrome progeroid type

Pathogenic:1Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 22, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 23, 2022	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 214 of the B4GALT7 protein (p.Cys214Tyr). This variant is present in population databases (rs753594601, gnomAD 0.007%). This missense change has been observed in individuals with clinical features of B4GALT7-associated Ehlers-Danlos syndrome (PMID: 26940150, 34193099). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 253110). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 21, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26940150, 31589614, 34193099, 25533962) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.68

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

M_CAP

Uncertain

0.19

MetaRNN

Pathogenic

0.91

MetaSVM

Uncertain

0.33

MutationAssessor

Uncertain

2.2

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.96

PROVEAN

Uncertain

-2.9

REVEL

Pathogenic

0.85

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.0060

Polyphen

0.91

Vest4

0.99

MutPred

0.59

Gain of MoRF binding (P = 0.072);

MVP

0.94

MPC

0.84

ClinPred

0.74

GERP RS

5.4

Varity_R

0.96

gMVP

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.94

dbscSNV1_RF

Benign

0.62

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over