chr22-24611096-A-T

Position:

chr22-24611096-A-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM2PP2BP4_StrongBP6_Moderate

The NM_001288833.2(GGT1):c.15A>T(p.Leu5Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000197 in 152,146 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GGT1
NM_001288833.2 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.78

Variant links:

Genes affected

GGT1 (HGNC:4250): (gamma-glutamyltransferase 1) The enzyme encoded by this gene is a type I gamma-glutamyltransferase that catalyzes the transfer of the glutamyl moiety of glutathione to a variety of amino acids and dipeptide acceptors. The enzyme is composed of a heavy chain and a light chain, which are derived from a single precursor protein. It is expressed in tissues involved in absorption and secretion and may contribute to the etiology of diabetes and other metabolic disorders. Multiple alternatively spliced variants have been identified. There are a number of related genes present on chromosomes 20 and 22, and putative pseudogenes for this gene on chromosomes 2, 13, and 22. [provided by RefSeq, Jan 2014]

GGT1 links:

ENSG00000286070 (HGNC:):

ENSG00000286070 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), GGT1. . Gene score misZ 0.85745 (greater than the threshold 3.09). Trascript score misZ 3.5416 (greater than threshold 3.09). GenCC has associacion of gene with gamma-glutamyl transpeptidase deficiency.

BP4

Computational evidence support a benign effect (MetaRNN=0.037744224).

BP6

Variant 22-24611096-A-T is Benign according to our data. Variant chr22-24611096-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 2324927.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GGT1	NM_001288833.2 linkuse as main transcript	c.15A>T	p.Leu5Phe	missense_variant	5/16	ENST00000400382.6	NP_001275762.1	P19440-1A0A140VJJ9
GGT1	NM_013421.3 linkuse as main transcript	c.15A>T	p.Leu5Phe	missense_variant	6/17		NP_038265.2	P19440-1A0A140VJJ9
GGT1	NM_013430.3 linkuse as main transcript	c.15A>T	p.Leu5Phe	missense_variant	5/16		NP_038347.2	P19440-1A0A140VJJ9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
GGT1	ENST00000400382.6 linkuse as main transcript	c.15A>T	p.Leu5Phe	missense_variant	5/16	2	NM_001288833.2	ENSP00000383232.1	P19440-1
ENSG00000286070	ENST00000652248.1 linkuse as main transcript	n.*505A>T		non_coding_transcript_exon_variant	9/20			ENSP00000499210.1
ENSG00000286070	ENST00000652248.1 linkuse as main transcript	n.*505A>T		3_prime_UTR_variant	9/20			ENSP00000499210.1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000138

AC:

AN:

1451496

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

721268

show subpopulations

Gnomad4 AFR exome

AF:

0.0000602

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 09, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.62

CADD

Benign

0.0020

DANN

Benign

0.73

DEOGEN2

Benign

0.13

T;.;.;.;.;T;T;.;T;.;T;.;.;.;.;.;.

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.0029

LIST_S2

Benign

0.42

.;T;T;T;T;T;.;T;T;T;T;T;T;.;T;T;T

M_CAP

Benign

0.0027

MetaRNN

Benign

0.038

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.39

N;.;.;.;.;.;N;.;.;.;N;.;.;.;.;.;.

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.030

N;D;N;N;N;N;N;D;N;N;N;N;N;N;N;N;N

REVEL

Benign

0.014

Sift

Benign

0.67

T;.;T;T;T;T;T;.;T;T;T;T;T;T;T;T;T

Sift4G

Benign

0.69

T;D;T;T;T;T;T;D;T;T;T;T;T;T;T;T;T

Polyphen

0.0

B;.;.;.;.;.;B;.;.;.;B;.;.;.;.;.;.

Vest4

0.046

MutPred

0.33

Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);

MVP

0.19

ClinPred

0.015

GERP RS

-6.5

Varity_R

0.033

gMVP

0.40

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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