chr9-34648091-G-A

Variant names:

• chr9-34648091-G-A
• rs41274867
• NM_000155.4:c.508-24G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_000155.4(GALT):​c.508-24G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0599 in 1,614,124 control chromosomes in the GnomAD database, including 3,191 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.047 (261 hom., cov: 32)
  • Exomes 𝑓: 0.061 (2930 hom.)
• Consequence: GALT NM_000155.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 B:11 O:1
• Conservation: PhyloP100: 0.257
• Publications: 17 publications found

Genes affected

GALT (HGNC:4135): (galactose-1-phosphate uridylyltransferase) Galactose-1-phosphate uridyl transferase (GALT) catalyzes the second step of the Leloir pathway of galactose metabolism, namely the conversion of UDP-glucose + galactose-1-phosphate to glucose-1-phosphate + UDP-galactose. The absence of this enzyme results in classic galactosemia in humans and can be fatal in the newborn period if lactose is not removed from the diet. The pathophysiology of galactosemia has not been clearly defined. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

GALT Gene-Disease associations (from GenCC):

• classic galactosemia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• galactosemia

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, Myriad Women’s Health

ENSG00000258728 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 9-34648091-G-A is Benign according to our data. Variant chr9-34648091-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 25195.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.063 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000155.4. 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
	GALT	NM_000155.4	MANE Select	c.508-24G>A		intron	N/A	NP_000146.2
	GALT	NM_001258332.2		c.181-24G>A		intron	N/A	NP_001245261.1	P07902-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALT	ENST00000378842.8	TSL:1 MANE Select	c.508-24G>A		intron	N/A	ENSP00000368119.4	P07902-1
	ENSG00000258728	ENST00000556278.1	TSL:5	c.253-24G>A		intron	N/A	ENSP00000451792.1	G3V4G9
	GALT	ENST00000902340.1		c.547-24G>A		intron	N/A	ENSP00000572399.1

Frequencies

GnomAD3 genomes AF: 0.0469 AC: 7135 AN: 152130 Hom.: 260 Cov.: 32

Gnomad AFR AF: 0.0123

Gnomad AMI AF: 0.164

Gnomad AMR AF: 0.0487

Gnomad ASJ AF: 0.0481

Gnomad EAS AF: 0.00926

Gnomad SAS AF: 0.0693

Gnomad FIN AF: 0.0672

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0642

Gnomad OTH AF: 0.0436

GnomAD2 exomes AF: 0.0543 AC: 13647 AN: 251494 AF XY: 0.0565

Gnomad AFR exome AF: 0.0125

Gnomad AMR exome AF: 0.0472

Gnomad ASJ exome AF: 0.0512

Gnomad EAS exome AF: 0.00870

Gnomad FIN exome AF: 0.0687

Gnomad NFE exome AF: 0.0613

Gnomad OTH exome AF: 0.0599

GnomAD4 exome AF: 0.0613 AC: 89593 AN: 1461876 Hom.: 2930 Cov.: 33 AF XY: 0.0618 AC XY: 44973 AN XY: 727238

African (AFR) AF: 0.0103 AC: 345 AN: 33480

American (AMR) AF: 0.0480 AC: 2145 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0512 AC: 1338 AN: 26136

East Asian (EAS) AF: 0.00645 AC: 256 AN: 39700

South Asian (SAS) AF: 0.0755 AC: 6511 AN: 86258

European-Finnish (FIN) AF: 0.0678 AC: 3623 AN: 53418

Middle Eastern (MID) AF: 0.0465 AC: 268 AN: 5768

European-Non Finnish (NFE) AF: 0.0644 AC: 71594 AN: 1111998

Other (OTH) AF: 0.0582 AC: 3513 AN: 60394

GnomAD4 genome AF: 0.0469 AC: 7137 AN: 152248 Hom.: 261 Cov.: 32 AF XY: 0.0467 AC XY: 3476 AN XY: 74440

African (AFR) AF: 0.0123 AC: 509 AN: 41548

American (AMR) AF: 0.0488 AC: 746 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0481 AC: 167 AN: 3472

East Asian (EAS) AF: 0.00908 AC: 47 AN: 5174

South Asian (SAS) AF: 0.0691 AC: 333 AN: 4818

European-Finnish (FIN) AF: 0.0672 AC: 713 AN: 10608

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0642 AC: 4368 AN: 68014

Other (OTH) AF: 0.0441 AC: 93 AN: 2108

Alfa AF: 0.0528 Hom.: 390

Bravo AF: 0.0421

Asia WGS AF: 0.0340 AC: 118 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	5	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase (7)
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Galactosemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.8
DANN	Benign	0.79
PhyloP100		0.26
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: rs41274867; hg19: chr9-34648088; COSMIC: COSV66592719; COSMIC: COSV66592719;