rs17454674

Variant names:

• chr12-57626799-G-A
• rs17454674
• NM_001478.5:c.1547C>T

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.1547C>T​(p.Ala516Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00961 in 1,614,208 control chromosomes in the GnomAD database, including 89 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.0073 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0099 (86 hom.)
• Consequence: B4GALNT1 NM_001478.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.92
• Publications: 13 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=0.003937304).
• BP6: Variant 12-57626799-G-A is Benign according to our data. Variant chr12-57626799-G-A is described in ClinVar as Benign. ClinVar VariationId is 235331.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00735 (1119/152322) while in subpopulation NFE AF = 0.0116 (788/68016). AF 95% confidence interval is 0.0109. There are 3 homozygotes in GnomAd4. There are 534 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.1547C>T	p.Ala516Val	missense	Exon 11 of 11	NP_001469.1	Q00973-1
	B4GALNT1	NM_001413967.1		c.1715C>T	p.Ala572Val	missense	Exon 11 of 11	NP_001400896.1
	B4GALNT1	NM_001413968.1		c.1682C>T	p.Ala561Val	missense	Exon 11 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.1547C>T	p.Ala516Val	missense	Exon 11 of 11	ENSP00000341562.4	Q00973-1
	B4GALNT1	ENST00000882412.1		c.1682C>T	p.Ala561Val	missense	Exon 11 of 11	ENSP00000552471.1
	B4GALNT1	ENST00000954202.1		c.1547C>T	p.Ala516Val	missense	Exon 10 of 10	ENSP00000624261.1

Frequencies

GnomAD3 genomes AF: 0.00736 AC: 1120 AN: 152204 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00171

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00366

Gnomad ASJ AF: 0.0135

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.0137

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0116

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00741 AC: 1864 AN: 251486 AF XY: 0.00734

Gnomad AFR exome AF: 0.00141

Gnomad AMR exome AF: 0.00283

Gnomad ASJ exome AF: 0.0106

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0150

Gnomad NFE exome AF: 0.0109

Gnomad OTH exome AF: 0.00863

GnomAD4 exome AF: 0.00985 AC: 14401 AN: 1461886 Hom.: 86 Cov.: 31 AF XY: 0.00971 AC XY: 7062 AN XY: 727246

African (AFR) AF: 0.00134 AC: 45 AN: 33480

American (AMR) AF: 0.00288 AC: 129 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0119 AC: 311 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000719 AC: 62 AN: 86258

European-Finnish (FIN) AF: 0.0154 AC: 820 AN: 53420

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.0112 AC: 12504 AN: 1112006

Other (OTH) AF: 0.00866 AC: 523 AN: 60396

GnomAD4 genome AF: 0.00735 AC: 1119 AN: 152322 Hom.: 3 Cov.: 32 AF XY: 0.00717 AC XY: 534 AN XY: 74484

African (AFR) AF: 0.00171 AC: 71 AN: 41582

American (AMR) AF: 0.00366 AC: 56 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0135 AC: 47 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000828 AC: 4 AN: 4830

European-Finnish (FIN) AF: 0.0137 AC: 145 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0116 AC: 788 AN: 68016

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00956 Hom.: 43

Bravo AF: 0.00598

TwinsUK AF: 0.0102 AC: 38

ALSPAC AF: 0.00882 AC: 34

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.00849 AC: 73

ExAC AF: 0.00749 AC: 909

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00943

EpiControl AF: 0.00818

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	21
DANN	Benign	0.95
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.086
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L
PhyloP100		2.9
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.10	N
REVEL	Benign	0.039
Sift	Benign	0.56	T
Sift4G	Benign	1.0	T
Polyphen		0.017	B
Vest4		0.062
MVP		0.22
MPC		0.91
ClinPred		0.0091	T
GERP RS		4.6
Varity_R		0.063
gMVP		0.36
Mutation Taster		=97/3	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: rs17454674; hg19: chr12-58020582; COSMIC: COSV57543685; COSMIC: COSV57543685;