NM_001478.5:c.514G>C

Variant names:

• chr12-57630495-C-G
• rs810205
• NM_001478.5:c.514G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001478.5(B4GALNT1):​c.514G>C​(p.Gly172Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0192 in 1,609,128 control chromosomes in the GnomAD database, including 397 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G172S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.028 (84 hom., cov: 33)
  • Exomes 𝑓: 0.018 (313 hom.)
• Consequence: B4GALNT1 NM_001478.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.526
• Publications: 11 publications found

Genes affected

B4GALNT1 (HGNC:4117): (beta-1,4-N-acetyl-galactosaminyltransferase 1) GM2 and GD2 gangliosides are sialic acid-containing glycosphingolipids. GalNAc-T is the enzyme involved in the biosynthesis of G(M2) and G(D2) glycosphingolipids. GalNAc-T catalyzes the transfer of GalNAc into G(M3) and G(D3) by a beta-1,4 linkage, resulting in the synthesis of G(M2) and G(D2), respectively. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2013]

B4GALNT1 Gene-Disease associations (from GenCC):

• complex hereditary spastic paraplegia

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hereditary spastic paraplegia 26

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021012425).
• BP6: Variant 12-57630495-C-G is Benign according to our data. Variant chr12-57630495-C-G is described in ClinVar as Benign. ClinVar VariationId is 380791.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0279 (4244/152302) while in subpopulation AFR AF = 0.0485 (2014/41554). AF 95% confidence interval is 0.0467. There are 84 homozygotes in GnomAd4. There are 2156 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 84 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001478.5. 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
	B4GALNT1	NM_001478.5	MANE Select	c.514G>C	p.Gly172Arg	missense	Exon 5 of 11	NP_001469.1	Q00973-1
	B4GALNT1	NM_001413967.1		c.514G>C	p.Gly172Arg	missense	Exon 5 of 11	NP_001400896.1
	B4GALNT1	NM_001413968.1		c.514G>C	p.Gly172Arg	missense	Exon 5 of 11	NP_001400897.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	B4GALNT1	ENST00000341156.9	TSL:1 MANE Select	c.514G>C	p.Gly172Arg	missense	Exon 5 of 11	ENSP00000341562.4	Q00973-1
	B4GALNT1	ENST00000550764.5	TSL:1	c.514G>C	p.Gly172Arg	missense	Exon 5 of 6	ENSP00000450303.1	Q00973-3
	B4GALNT1	ENST00000882412.1		c.514G>C	p.Gly172Arg	missense	Exon 5 of 11	ENSP00000552471.1

Frequencies

GnomAD3 genomes AF: 0.0279 AC: 4241 AN: 152184 Hom.: 83 Cov.: 33

Gnomad AFR AF: 0.0485

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0122

Gnomad ASJ AF: 0.0245

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0180

Gnomad FIN AF: 0.0503

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0189

Gnomad OTH AF: 0.0215

GnomAD2 exomes AF: 0.0191 AC: 4719 AN: 246592 AF XY: 0.0188

Gnomad AFR exome AF: 0.0461

Gnomad AMR exome AF: 0.00637

Gnomad ASJ exome AF: 0.0247

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0461

Gnomad NFE exome AF: 0.0165

Gnomad OTH exome AF: 0.0180

GnomAD4 exome AF: 0.0183 AC: 26593 AN: 1456826 Hom.: 313 Cov.: 32 AF XY: 0.0182 AC XY: 13168 AN XY: 724394

African (AFR) AF: 0.0490 AC: 1630 AN: 33284

American (AMR) AF: 0.00751 AC: 330 AN: 43966

Ashkenazi Jewish (ASJ) AF: 0.0234 AC: 602 AN: 25746

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39660

South Asian (SAS) AF: 0.0193 AC: 1651 AN: 85398

European-Finnish (FIN) AF: 0.0445 AC: 2370 AN: 53234

Middle Eastern (MID) AF: 0.0318 AC: 182 AN: 5718

European-Non Finnish (NFE) AF: 0.0168 AC: 18651 AN: 1109626

Other (OTH) AF: 0.0195 AC: 1172 AN: 60194

GnomAD4 genome AF: 0.0279 AC: 4244 AN: 152302 Hom.: 84 Cov.: 33 AF XY: 0.0290 AC XY: 2156 AN XY: 74466

African (AFR) AF: 0.0485 AC: 2014 AN: 41554

American (AMR) AF: 0.0121 AC: 186 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0245 AC: 85 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.0178 AC: 86 AN: 4824

European-Finnish (FIN) AF: 0.0503 AC: 534 AN: 10608

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0189 AC: 1289 AN: 68024

Other (OTH) AF: 0.0213 AC: 45 AN: 2112

Alfa AF: 0.0170 Hom.: 23

Bravo AF: 0.0253

TwinsUK AF: 0.0143 AC: 53

ALSPAC AF: 0.0132 AC: 51

ESP6500AA AF: 0.0497 AC: 219

ESP6500EA AF: 0.0180 AC: 155

ExAC AF: 0.0198 AC: 2399

Asia WGS AF: 0.0110 AC: 37 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	16
DANN	Benign	0.94
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.12	N
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.53
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.50	N
REVEL	Benign	0.12
Sift	Benign	0.12	T
Sift4G	Benign	0.58	T
Polyphen		0.0	B
Vest4		0.22
MPC		0.31
ClinPred		0.014	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.12
gMVP		0.66
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs810205; hg19: chr12-58024278;