14-87986637-C-T

Variant names:

• chr14-87986637-C-T
• rs77466023
• NM_000153.4:c.329-35G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000153.4(GALC):​c.329-35G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.138 in 1,314,266 control chromosomes in the GnomAD database, including 13,862 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1139 hom., cov: 31)
  • Exomes 𝑓: 0.14 (12723 hom.)
• Consequence: GALC NM_000153.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.131
• Publications: 11 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: G2P, Myriad Women’s Health, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, Genomics England PanelApp

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 14-87986637-C-T is Benign according to our data. Variant chr14-87986637-C-T is described in ClinVar as Benign. ClinVar VariationId is 255375.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.154 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALC	NM_000153.4	c.329-35G>A		intron_variant	Intron 3 of 16	ENST00000261304.7	NP_000144.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALC	ENST00000261304.7	c.329-35G>A		intron_variant	Intron 3 of 16	1	NM_000153.4	ENSP00000261304.2

Frequencies

GnomAD3 genomes AF: 0.113 AC: 17102 AN: 151750 Hom.: 1136 Cov.: 31

Gnomad AFR AF: 0.0398

Gnomad AMI AF: 0.140

Gnomad AMR AF: 0.129

Gnomad ASJ AF: 0.119

Gnomad EAS AF: 0.00232

Gnomad SAS AF: 0.0954

Gnomad FIN AF: 0.154

Gnomad MID AF: 0.125

Gnomad NFE AF: 0.156

Gnomad OTH AF: 0.109

GnomAD2 exomes AF: 0.127 AC: 30189 AN: 237698 AF XY: 0.127

Gnomad AFR exome AF: 0.0377

Gnomad AMR exome AF: 0.145

Gnomad ASJ exome AF: 0.116

Gnomad EAS exome AF: 0.00247

Gnomad FIN exome AF: 0.159

Gnomad NFE exome AF: 0.156

Gnomad OTH exome AF: 0.133

GnomAD4 exome AF: 0.142 AC: 164569 AN: 1162398 Hom.: 12723 Cov.: 16 AF XY: 0.140 AC XY: 83213 AN XY: 592304

African (AFR) AF: 0.0362 AC: 991 AN: 27378

American (AMR) AF: 0.146 AC: 6361 AN: 43532

Ashkenazi Jewish (ASJ) AF: 0.117 AC: 2842 AN: 24238

East Asian (EAS) AF: 0.00170 AC: 65 AN: 38308

South Asian (SAS) AF: 0.102 AC: 8129 AN: 79612

European-Finnish (FIN) AF: 0.162 AC: 8529 AN: 52576

Middle Eastern (MID) AF: 0.163 AC: 842 AN: 5160

European-Non Finnish (NFE) AF: 0.155 AC: 130155 AN: 841114

Other (OTH) AF: 0.132 AC: 6655 AN: 50480

GnomAD4 genome AF: 0.113 AC: 17111 AN: 151868 Hom.: 1139 Cov.: 31 AF XY: 0.113 AC XY: 8377 AN XY: 74184

African (AFR) AF: 0.0398 AC: 1651 AN: 41460

American (AMR) AF: 0.129 AC: 1965 AN: 15202

Ashkenazi Jewish (ASJ) AF: 0.119 AC: 414 AN: 3470

East Asian (EAS) AF: 0.00233 AC: 12 AN: 5154

South Asian (SAS) AF: 0.0953 AC: 459 AN: 4818

European-Finnish (FIN) AF: 0.154 AC: 1614 AN: 10502

Middle Eastern (MID) AF: 0.121 AC: 35 AN: 290

European-Non Finnish (NFE) AF: 0.156 AC: 10605 AN: 67946

Other (OTH) AF: 0.108 AC: 228 AN: 2114

Alfa AF: 0.134 Hom.: 308

Bravo AF: 0.107

Asia WGS AF: 0.0550 AC: 192 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Galactosylceramide beta-galactosidase deficiency Benign:1

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	10
DANN	Benign	0.65
PhyloP100		0.13
Mutation Taster		=100/0	polymorphism (auto)

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: rs77466023; hg19: chr14-88452981;