chr14-87992960-T-C

Variant names:

• chr14-87992960-T-C
• rs191767015
• NM_000153.4:c.195+10A>G

Variant summary

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

The NM_000153.4(GALC):​c.195+10A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00113 in 1,512,872 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0060 (13 hom., cov: 33)
  • Exomes 𝑓: 0.00058 (2 hom.)
• Consequence: GALC NM_000153.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.90
• Publications: 1 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=-0.9).
• BP6: Variant 14-87992960-T-C is Benign according to our data. Variant chr14-87992960-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 456716.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 = 0.00604 (920/152230) while in subpopulation AFR AF = 0.0212 (883/41562). AF 95% confidence interval is 0.0201. There are 13 homozygotes in GnomAd4. There are 437 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALC	NM_000153.4	MANE Select	c.195+10A>G		intron	N/A	NP_000144.2
	GALC	NM_001201401.2		c.195+10A>G		intron	N/A	NP_001188330.1
	GALC	NM_001201402.2		c.117+423A>G		intron	N/A	NP_001188331.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALC	ENST00000261304.7	TSL:1 MANE Select	c.195+10A>G		intron	N/A	ENSP00000261304.2
	GALC	ENST00000622264.4	TSL:1	c.183+10A>G		intron	N/A	ENSP00000480649.1
	GALC	ENST00000474294.6	TSL:1	n.185+10A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00603 AC: 917 AN: 152122 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.0212

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.000392 AC: 46 AN: 117494 AF XY: 0.000227

Gnomad AFR exome AF: 0.0129

Gnomad AMR exome AF: 0.000341

Gnomad ASJ exome AF: 0.000559

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000634

Gnomad OTH exome AF: 0.000299

GnomAD4 exome AF: 0.000575 AC: 783 AN: 1360642 Hom.: 2 Cov.: 33 AF XY: 0.000500 AC XY: 336 AN XY: 672246

African (AFR) AF: 0.0238 AC: 654 AN: 27500

American (AMR) AF: 0.000716 AC: 25 AN: 34906

Ashkenazi Jewish (ASJ) AF: 0.000460 AC: 11 AN: 23908

East Asian (EAS) AF: 0.00 AC: 0 AN: 31844

South Asian (SAS) AF: 0.0000260 AC: 2 AN: 76790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34064

Middle Eastern (MID) AF: 0.00151 AC: 6 AN: 3976

European-Non Finnish (NFE) AF: 0.0000233 AC: 25 AN: 1071270

Other (OTH) AF: 0.00106 AC: 60 AN: 56384

GnomAD4 genome AF: 0.00604 AC: 920 AN: 152230 Hom.: 13 Cov.: 33 AF XY: 0.00587 AC XY: 437 AN XY: 74430

African (AFR) AF: 0.0212 AC: 883 AN: 41562

American (AMR) AF: 0.00144 AC: 22 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 67974

Other (OTH) AF: 0.00332 AC: 7 AN: 2110

Alfa AF: 0.00450 Hom.: 1

Bravo AF: 0.00699

Asia WGS AF: 0.00116 AC: 4 AN: 3470

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Galactosylceramide beta-galactosidase deficiency (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.3
DANN	Benign	0.35
PhyloP100		-1.9
PromoterAI		0.016	Neutral
Mutation Taster		=100/0	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: rs191767015; hg19: chr14-88459304;