chr9-34649456-G-T

Position:

• chr9-34649456-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PS1_Moderate PM2 PM5 PP3_Moderate

The NM_000155.4(GALT):​c.951G>T​(p.Gln317His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q317R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: GALT NM_000155.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.405

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PS1: Transcript NM_000155.4 (GALT) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.932

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GALT	NM_000155.4	c.951G>T	p.Gln317His	missense_variant	10/11	ENST00000378842.8	NP_000146.2
GALT	NM_001258332.2	c.624G>T	p.Gln208His	missense_variant	8/9		NP_001245261.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GALT	ENST00000378842.8	c.951G>T	p.Gln317His	missense_variant	10/11	1	NM_000155.4	ENSP00000368119	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.40
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.89	.;D
Eigen	Benign	0.046
Eigen_PC	Benign	0.088
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Benign	1.6	.;L
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-4.5	D;D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.019	D;D
Sift4G	Benign	0.25	T;T
Polyphen		0.88	.;P
Vest4		0.66
MutPred		0.93		.;Loss of catalytic residue at Q317 (P = 0.0763);
MVP		0.98
MPC		0.32
ClinPred		0.96	D
GERP RS		3.5
Varity_R		0.80
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs111033787; hg19: chr9-34649453;