chr5-177600223-C-T

Variant names:

• chr5-177600223-C-T
• rs2127509643
• NM_007255.3:c.13C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_007255.3(B4GALT7):​c.13C>T​(p.Arg5Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000322 in 1,241,084 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. R5R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000032 (0 hom.)
• Consequence: B4GALT7 NM_007255.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.09
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Ehlers-Danlos syndrome, spondylodysplastic type, 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P, Ambry Genetics
• Ehlers-Danlos syndrome, spondylodysplastic type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
B4GALT7	NM_007255.3	c.13C>T	p.Arg5Trp	missense_variant	Exon 1 of 6	ENST00000029410.10	NP_009186.1
B4GALT7	XM_047416681.1	c.-1098C>T		5_prime_UTR_variant	Exon 1 of 7		XP_047272637.1
B4GALT7	XM_047416682.1	c.-383C>T		5_prime_UTR_variant	Exon 1 of 7		XP_047272638.1
B4GALT7	XM_047416680.1	c.-2263C>T		upstream_gene_variant			XP_047272636.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
B4GALT7	ENST00000029410.10	c.13C>T	p.Arg5Trp	missense_variant	Exon 1 of 6	1	NM_007255.3	ENSP00000029410.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000322 AC: 4 AN: 1241084 Hom.: 0 Cov.: 30 AF XY: 0.00000329 AC XY: 2 AN XY: 608070

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 25672

American (AMR) AF: 0.0000439 AC: 1 AN: 22798

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21260

East Asian (EAS) AF: 0.00 AC: 0 AN: 27510

South Asian (SAS) AF: 0.00 AC: 0 AN: 61110

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29762

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3572

European-Non Finnish (NFE) AF: 0.00000300 AC: 3 AN: 999256

Other (OTH) AF: 0.00 AC: 0 AN: 50144

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.005859), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Uncertain:1

Nov 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 5 of the B4GALT7 protein (p.Arg5Trp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with B4GALT7-related conditions. ClinVar contains an entry for this variant (Variation ID: 1347751). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.083	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.070	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		3.1
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.44
MutPred		0.38		Loss of disorder (P = 0.0043);
MVP		0.87
MPC		0.51
ClinPred		0.99	D
GERP RS		4.2
PromoterAI		-0.13	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.33
gMVP		0.78
Mutation Taster		=81/19	polymorphism

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

Other links and lift over

dbSNP: rs2127509643; hg19: chr5-177027224;