5-177600256-G-C

Variant names:

• chr5-177600256-G-C
• rs1391741493
• NM_007255.3:c.46G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_007255.3(B4GALT7):​c.46G>C​(p.Gly16Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,210,490 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000025 (0 hom.)
• Consequence: B4GALT7 NM_007255.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.57
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14076003).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
B4GALT7	NM_007255.3	c.46G>C	p.Gly16Arg	missense_variant	Exon 1 of 6	ENST00000029410.10	NP_009186.1
B4GALT7	XM_047416681.1	c.-1065G>C		5_prime_UTR_variant	Exon 1 of 7		XP_047272637.1
B4GALT7	XM_047416682.1	c.-350G>C		5_prime_UTR_variant	Exon 1 of 7		XP_047272638.1
B4GALT7	XM_047416680.1	c.-2230G>C		upstream_gene_variant			XP_047272636.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
B4GALT7	ENST00000029410.10	c.46G>C	p.Gly16Arg	missense_variant	Exon 1 of 6	1	NM_007255.3	ENSP00000029410.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000248 AC: 3 AN: 1210490 Hom.: 0 Cov.: 30 AF XY: 0.00000339 AC XY: 2 AN XY: 590448

African (AFR) AF: 0.00 AC: 0 AN: 24644

American (AMR) AF: 0.0000550 AC: 1 AN: 18180

Ashkenazi Jewish (ASJ) AF: 0.0000504 AC: 1 AN: 19852

East Asian (EAS) AF: 0.00 AC: 0 AN: 27280

South Asian (SAS) AF: 0.00 AC: 0 AN: 56584

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28442

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3454

European-Non Finnish (NFE) AF: 0.00000102 AC: 1 AN: 983304

Other (OTH) AF: 0.00 AC: 0 AN: 48750

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

B4GALT7: PM2 -

Uncertain:1

Jan 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 16 of the B4GALT7 protein (p.Gly16Arg). 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: 1176500). 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 tolerated. 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	0.085
BayesDel_addAF	Benign	-0.044	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.015	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.75	T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.7	L
PhyloP100		1.6
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.079
Sift	Benign	0.14	T
Sift4G	Benign	0.091	T
Polyphen		0.0010	B
Vest4		0.17
MutPred		0.18		Loss of loop (P = 0.0203);
MVP		0.68
MPC		0.18
ClinPred		0.44	T
GERP RS		3.1
PromoterAI		0.022	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.13
gMVP		0.24
Mutation Taster		=80/20	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: rs1391741493; hg19: chr5-177027257;