22-42692966-G-A

Position:

chr22-42692966-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_017436.7(A4GALT):c.986C>T(p.Thr329Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000887 in 1,612,600 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000095 ( 0 hom. )

Consequence

A4GALT
NM_017436.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.49

Variant links:

Genes affected

A4GALT (HGNC:18149): (alpha 1,4-galactosyltransferase (P1PK blood group)) The protein encoded by this gene catalyzes the transfer of galactose to lactosylceramide to form globotriaosylceramide, which has been identified as the P(k) antigen of the P blood group system. This protein, a type II membrane protein found in the Golgi, is also required for the synthesis of the bacterial verotoxins receptor. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Dec 2015]

A4GALT links:

CYB5R3 (HGNC:2873): (cytochrome b5 reductase 3) This gene encodes cytochrome b5 reductase, which includes a membrane-bound form in somatic cells (anchored in the endoplasmic reticulum, mitochondrial and other membranes) and a soluble form in erythrocytes. The membrane-bound form exists mainly on the cytoplasmic side of the endoplasmic reticulum and functions in desaturation and elongation of fatty acids, in cholesterol biosynthesis, and in drug metabolism. The erythrocyte form is located in a soluble fraction of circulating erythrocytes and is involved in methemoglobin reduction. The membrane-bound form has both membrane-binding and catalytic domains, while the soluble form has only the catalytic domain. Alternate splicing results in multiple transcript variants. Mutations in this gene cause methemoglobinemias. [provided by RefSeq, Jan 2010]

CYB5R3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.27752852).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
A4GALT	NM_017436.7 linkuse as main transcript	c.986C>T	p.Thr329Met	missense_variant	3/3	ENST00000642412.2	NP_059132.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
A4GALT	ENST00000642412.2 linkuse as main transcript	c.986C>T	p.Thr329Met	missense_variant	3/3		NM_017436.7	ENSP00000494127	P1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000172

AC:

AN:

250014

Hom.:

AF XY:

0.000192

AC XY:

AN XY:

135486

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00124

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000952

AC:

139

AN:

1460400

Hom.:

Cov.:

AF XY:

0.000125

AC XY:

AN XY:

726610

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00126

Gnomad4 FIN exome

AF:

0.0000192

Gnomad4 NFE exome

AF:

0.0000171

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000556

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.000189

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 27, 2022

The c.986C>T (p.T329M) alteration is located in exon 3 (coding exon 1) of the A4GALT gene. This alteration results from a C to T substitution at nucleotide position 986, causing the threonine (T) at amino acid position 329 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.31

T;T;T;T

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.82

.;.;T;.

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.28

T;T;T;T

MetaSVM

Uncertain

-0.14

MutationAssessor

Benign

1.9

L;L;L;L

MutationTaster

Benign

0.90

N;N;N

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.8

.;N;N;N

REVEL

Uncertain

0.48

Sift

Benign

0.086

.;T;T;T

Sift4G

Benign

0.11

.;T;T;T

Polyphen

1.0

D;D;D;D

Vest4

0.46, 0.46

MutPred

0.72

Gain of MoRF binding (P = 0.0683);Gain of MoRF binding (P = 0.0683);Gain of MoRF binding (P = 0.0683);Gain of MoRF binding (P = 0.0683);

MVP

0.92

MPC

0.55

ClinPred

0.043

GERP RS

5.3

Varity_R

0.27

gMVP

0.51

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over