rs780972896

Variant names:

• chr14-87993163-A-G
• rs780972896
• NM_000153.4:c.2T>C

Your query was ambiguous. Multiple possible variants found:

• chr14-87993163-A-G
• chr14-87993163-A-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_000153.4(GALC):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GALC NM_000153.4 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 2.16
• Publications: 3 publications found

Genes affected

GALC (HGNC:4115): (galactosylceramidase) This gene encodes a lysosomal protein which hydrolyzes the galactose ester bonds of galactosylceramide, galactosylsphingosine, lactosylceramide, and monogalactosyldiglyceride. Mutations in this gene have been associated with Krabbe disease, also known as globoid cell leukodystrophy. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

GALC Gene-Disease associations (from GenCC):

• Krabbe disease

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp, ClinGen, G2P, Labcorp Genetics (formerly Invitae), Myriad Women’s Health

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 12 pathogenic variants. Next in-frame start position is after 17 codons. Genomic position: 87993116. Lost 0.024 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000153.4. 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
	GALC	NM_000153.4	MANE Select	c.2T>C	p.Met1?	start_lost	Exon 1 of 17	NP_000144.2	P54803-1
	GALC	NM_001201401.2		c.2T>C	p.Met1?	start_lost	Exon 1 of 16	NP_001188330.1	P54803-3
	GALC	NM_001424072.1		c.-269T>C		5_prime_UTR	Exon 1 of 18	NP_001411001.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALC	ENST00000261304.7	TSL:1 MANE Select	c.2T>C	p.Met1?	start_lost	Exon 1 of 17	ENSP00000261304.2	P54803-1
	GALC	ENST00000921945.1		c.2T>C	p.Met1?	start_lost	Exon 1 of 16	ENSP00000592004.1
	GALC	ENST00000950382.1		c.2T>C	p.Met1?	start_lost	Exon 1 of 17	ENSP00000620441.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1438038 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 712896

African (AFR) AF: 0.00 AC: 0 AN: 33194

American (AMR) AF: 0.00 AC: 0 AN: 41694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25662

East Asian (EAS) AF: 0.00 AC: 0 AN: 38888

South Asian (SAS) AF: 0.00 AC: 0 AN: 82860

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49776

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1100686

Other (OTH) AF: 0.00 AC: 0 AN: 59536

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Galactosylceramide beta-galactosidase deficiency (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.058
FATHMM_MKL	Benign	0.27	N
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Benign	-1.0	T
PhyloP100		2.2
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.22
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.44	B
Vest4		0.70
MutPred		0.92		Gain of catalytic residue at M1 (P = 0.0028)
MVP		0.35
ClinPred		0.96	D
GERP RS		3.3
PromoterAI		-0.13	Neutral
Varity_R		0.81
gMVP		0.83
Mutation Taster		=94/106	disease causing (ClinVar)

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: rs780972896; hg19: chr14-88459507;