chr14-87986597-T-C

Variant names:

• chr14-87986597-T-C
• rs147313927
• NM_000153.4:c.334A>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 4P and 5B. PM1 PP2 PP5 BP4 BS2

The NM_000153.4(GALC):​c.334A>G​(p.Thr112Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00378 in 1,608,454 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T112P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (22 hom.)
• Consequence: GALC NM_000153.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:10 U:18 O:1
• Conservation: PhyloP100: 7.99
• Publications: 22 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: Likely_benign. The variant received -1 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000153.4
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 94 curated pathogenic missense variants (we use a threshold of 10). The gene has 16 curated benign missense variants. Gene score misZ: 0.18582 (below the threshold of 3.09). Trascript score misZ: -0.28853 (below the threshold of 3.09). GenCC associations: The gene is linked to Krabbe disease.
• PP5: Variant 14-87986597-T-C is Pathogenic according to our data. Variant chr14-87986597-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 92503.
• BP4: Computational evidence support a benign effect (MetaRNN=0.06605202). . Strength limited to SUPPORTING due to the PP5.
• BS2: High Homozygotes in GnomAdExome4 at 22 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALC	NM_000153.4	MANE Select	c.334A>G	p.Thr112Ala	missense	Exon 4 of 17	NP_000144.2	P54803-1
	GALC	NM_001201401.2		c.265A>G	p.Thr89Ala	missense	Exon 3 of 16	NP_001188330.1	P54803-3
	GALC	NM_001201402.2		c.256A>G	p.Thr86Ala	missense	Exon 4 of 17	NP_001188331.1	P54803-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALC	ENST00000261304.7	TSL:1 MANE Select	c.334A>G	p.Thr112Ala	missense	Exon 4 of 17	ENSP00000261304.2	P54803-1
	GALC	ENST00000622264.4	TSL:1	c.322A>G	p.Thr108Ala	missense	Exon 4 of 10	ENSP00000480649.1	A0A087WX10
	GALC	ENST00000474294.6	TSL:1	n.324A>G		non_coding_transcript_exon	Exon 4 of 10

Frequencies

GnomAD3 genomes AF: 0.00221 AC: 336 AN: 152098 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000590

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00393

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00253 AC: 629 AN: 248976 AF XY: 0.00269

Gnomad AFR exome AF: 0.000582

Gnomad AMR exome AF: 0.000987

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.00242

Gnomad NFE exome AF: 0.00407

Gnomad OTH exome AF: 0.00215

GnomAD4 exome AF: 0.00395 AC: 5745 AN: 1456238 Hom.: 22 Cov.: 29 AF XY: 0.00394 AC XY: 2855 AN XY: 724896

African (AFR) AF: 0.000660 AC: 22 AN: 33342

American (AMR) AF: 0.00107 AC: 48 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.0000766 AC: 2 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.00192 AC: 165 AN: 86142

European-Finnish (FIN) AF: 0.00266 AC: 142 AN: 53374

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5762

European-Non Finnish (NFE) AF: 0.00469 AC: 5190 AN: 1106940

Other (OTH) AF: 0.00289 AC: 174 AN: 60216

GnomAD4 genome AF: 0.00221 AC: 337 AN: 152216 Hom.: 1 Cov.: 32 AF XY: 0.00211 AC XY: 157 AN XY: 74424

African (AFR) AF: 0.000650 AC: 27 AN: 41554

American (AMR) AF: 0.000589 AC: 9 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

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

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4824

European-Finnish (FIN) AF: 0.00207 AC: 22 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00393 AC: 267 AN: 68004

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.00312 Hom.: 4

Bravo AF: 0.00220

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00727 AC: 28

ESP6500AA AF: 0.000500 AC: 2

ESP6500EA AF: 0.00373 AC: 31

ExAC AF: 0.00254 AC: 307

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00474

EpiControl AF: 0.00433

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
7	8	-	Galactosylceramide beta-galactosidase deficiency (16)
3	9	-	not provided (12)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.44
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.066	T
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		8.0
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-2.7	D
REVEL	Pathogenic	0.90
Sift	Benign	0.39	T
Sift4G	Benign	0.16	T
Polyphen		0.99	D
Vest4		0.92
MVP		0.98
MPC		0.42
ClinPred		0.026	T
GERP RS		5.4
Varity_R		0.27
gMVP		0.91
Mutation Taster		=7/93	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: rs147313927; hg19: chr14-88452941; COSMIC: COSV99039390; COSMIC: COSV99039390;