chr14-87988125-A-T

Variant names:

• chr14-87988125-A-T
• rs74337989
• NM_000153.4:c.328+19T>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.328+19T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.141 in 1,593,908 control chromosomes in the GnomAD database, including 17,218 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1143 hom., cov: 32)
  • Exomes 𝑓: 0.14 (16075 hom.)
• Consequence: GALC NM_000153.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.821
• Publications: 14 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=-0.79).
• BP6: Variant 14-87988125-A-T is Benign according to our data. Variant chr14-87988125-A-T is described in ClinVar as Benign. ClinVar VariationId is 92501.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.

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.328+19T>A		intron	N/A	NP_000144.2
	GALC	NM_001201401.2		c.259+19T>A		intron	N/A	NP_001188330.1
	GALC	NM_001201402.2		c.250+19T>A		intron	N/A	NP_001188331.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALC	ENST00000261304.7	TSL:1 MANE Select	c.328+19T>A		intron	N/A	ENSP00000261304.2
	GALC	ENST00000622264.4	TSL:1	c.316+19T>A		intron	N/A	ENSP00000480649.1
	GALC	ENST00000474294.6	TSL:1	n.318+19T>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.113 AC: 17192 AN: 152106 Hom.: 1140 Cov.: 32

Gnomad AFR AF: 0.0399

Gnomad AMI AF: 0.140

Gnomad AMR AF: 0.130

Gnomad ASJ AF: 0.119

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.0950

Gnomad FIN AF: 0.156

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.156

Gnomad OTH AF: 0.109

GnomAD2 exomes AF: 0.126 AC: 31460 AN: 249142 AF XY: 0.126

Gnomad AFR exome AF: 0.0370

Gnomad AMR exome AF: 0.144

Gnomad ASJ exome AF: 0.115

Gnomad EAS exome AF: 0.00206

Gnomad FIN exome AF: 0.159

Gnomad NFE exome AF: 0.155

Gnomad OTH exome AF: 0.132

GnomAD4 exome AF: 0.144 AC: 207512 AN: 1441684 Hom.: 16075 Cov.: 28 AF XY: 0.143 AC XY: 102669 AN XY: 718598

African (AFR) AF: 0.0347 AC: 1149 AN: 33082

American (AMR) AF: 0.146 AC: 6527 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.118 AC: 3078 AN: 26000

East Asian (EAS) AF: 0.00167 AC: 66 AN: 39550

South Asian (SAS) AF: 0.102 AC: 8745 AN: 85846

European-Finnish (FIN) AF: 0.163 AC: 8656 AN: 53238

Middle Eastern (MID) AF: 0.162 AC: 926 AN: 5722

European-Non Finnish (NFE) AF: 0.156 AC: 170425 AN: 1093770

Other (OTH) AF: 0.133 AC: 7940 AN: 59770

GnomAD4 genome AF: 0.113 AC: 17201 AN: 152224 Hom.: 1143 Cov.: 32 AF XY: 0.113 AC XY: 8439 AN XY: 74412

African (AFR) AF: 0.0399 AC: 1660 AN: 41562

American (AMR) AF: 0.131 AC: 1997 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.119 AC: 414 AN: 3472

East Asian (EAS) AF: 0.00232 AC: 12 AN: 5180

South Asian (SAS) AF: 0.0949 AC: 457 AN: 4816

European-Finnish (FIN) AF: 0.156 AC: 1649 AN: 10588

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.156 AC: 10618 AN: 68000

Other (OTH) AF: 0.108 AC: 228 AN: 2106

Alfa AF: 0.0906 Hom.: 172

Bravo AF: 0.107

Asia WGS AF: 0.0560 AC: 193 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	2	Galactosylceramide beta-galactosidase deficiency (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	4.3
DANN	Benign	0.77
PhyloP100		0.82
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: rs74337989; hg19: chr14-88454469;