rs2070074

Variant names:

• chr9-34649445-A-G
• rs2070074
• NM_000155.4:c.940A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 3P and 12B. PM1 PP2 BP4_Strong BA1

The NM_000155.4(GALT):​c.940A>G​(p.Asn314Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0937 in 1,613,986 control chromosomes in the GnomAD database, including 8,067 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,other (no stars). Synonymous variant affecting the same amino acid position (i.e. N314N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.075 (589 hom., cov: 32)
  • Exomes 𝑓: 0.096 (7478 hom.)
• Consequence: GALT NM_000155.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity; other criteria provided, conflicting classifications P:8 U:1 B:12 O:2
• Conservation: PhyloP100: 1.74
• Publications: 175 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 -9 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_000155.4
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 104 curated pathogenic missense variants (we use a threshold of 10). The gene has 17 curated benign missense variants. Gene score misZ: 0.91493 (below the threshold of 3.09). Trascript score misZ: 1.8645 (below the threshold of 3.09). GenCC associations: The gene is linked to galactosemia, classic galactosemia.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0015891492).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.163 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.940A>G	p.Asn314Asp	missense	Exon 10 of 11	NP_000146.2
	GALT	NM_001258332.2		c.613A>G	p.Asn205Asp	missense	Exon 8 of 9	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.940A>G	p.Asn314Asp	missense	Exon 10 of 11	ENSP00000368119.4	P07902-1
	ENSG00000258728	ENST00000556278.1	TSL:5	c.432+989A>G		intron	N/A	ENSP00000451792.1	G3V4G9
	GALT	ENST00000902340.1		c.979A>G	p.Asn327Asp	missense	Exon 9 of 10	ENSP00000572399.1

Frequencies

GnomAD3 genomes AF: 0.0749 AC: 11385 AN: 152036 Hom.: 589 Cov.: 32

Gnomad AFR AF: 0.0240

Gnomad AMI AF: 0.226

Gnomad AMR AF: 0.0709

Gnomad ASJ AF: 0.109

Gnomad EAS AF: 0.0110

Gnomad SAS AF: 0.173

Gnomad FIN AF: 0.110

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0952

Gnomad OTH AF: 0.0793

GnomAD2 exomes AF: 0.0917 AC: 23055 AN: 251460 AF XY: 0.0981

Gnomad AFR exome AF: 0.0249

Gnomad AMR exome AF: 0.0640

Gnomad ASJ exome AF: 0.112

Gnomad EAS exome AF: 0.00919

Gnomad FIN exome AF: 0.109

Gnomad NFE exome AF: 0.0933

Gnomad OTH exome AF: 0.0987

GnomAD4 exome AF: 0.0956 AC: 139784 AN: 1461832 Hom.: 7478 Cov.: 32 AF XY: 0.0986 AC XY: 71699 AN XY: 727220

African (AFR) AF: 0.0230 AC: 771 AN: 33480

American (AMR) AF: 0.0656 AC: 2935 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.113 AC: 2965 AN: 26136

East Asian (EAS) AF: 0.00673 AC: 267 AN: 39700

South Asian (SAS) AF: 0.180 AC: 15532 AN: 86256

European-Finnish (FIN) AF: 0.108 AC: 5749 AN: 53402

Middle Eastern (MID) AF: 0.113 AC: 652 AN: 5768

European-Non Finnish (NFE) AF: 0.0945 AC: 105076 AN: 1111974

Other (OTH) AF: 0.0966 AC: 5837 AN: 60394

GnomAD4 genome AF: 0.0748 AC: 11385 AN: 152154 Hom.: 589 Cov.: 32 AF XY: 0.0760 AC XY: 5656 AN XY: 74394

African (AFR) AF: 0.0239 AC: 994 AN: 41514

American (AMR) AF: 0.0709 AC: 1083 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 376 AN: 3462

East Asian (EAS) AF: 0.0108 AC: 56 AN: 5170

South Asian (SAS) AF: 0.173 AC: 834 AN: 4816

European-Finnish (FIN) AF: 0.110 AC: 1168 AN: 10604

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.0952 AC: 6475 AN: 67984

Other (OTH) AF: 0.0794 AC: 168 AN: 2116

Alfa AF: 0.0858 Hom.: 2230

Bravo AF: 0.0654

TwinsUK AF: 0.101 AC: 373

ALSPAC AF: 0.0957 AC: 369

ESP6500AA AF: 0.0288 AC: 127

ESP6500EA AF: 0.0934 AC: 803

ExAC AF: 0.0920 AC: 11169

Asia WGS AF: 0.0760 AC: 263 AN: 3478

EpiCase AF: 0.0993

EpiControl AF: 0.0962

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity; other

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
5	-	7	Deficiency of UDPglucose-hexose-1-phosphate uridylyltransferase (13)
3	1	2	not provided (7)
-	-	1	Galactosemia (1)
-	-	1	GALT POLYMORPHISM (DUARTE, D2) (1)
-	-	1	GALT-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	18
DANN	Benign	0.77
DEOGEN2	Uncertain	0.53	D
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	-1.3	N
PhyloP100		1.7
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.69	N
REVEL	Uncertain	0.38
Sift	Benign	1.0	T
Sift4G	Benign	0.70	T
Polyphen		0.0	B
Vest4		0.10
MPC		0.053
ClinPred		0.0012	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.61
Mutation Taster		=88/12	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: rs2070074; hg19: chr9-34649442; COSMIC: COSV58840369; COSMIC: COSV58840369;