Genetic Variant GOT1L1:p.Arg295His (chr8-37935749-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_152413.3(GOT1L1):c.884G>A(p.Arg295His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000875 in 1,610,628 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000091 ( 0 hom. )

Consequence

GOT1L1
NM_152413.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.52

Variant links:

Genes affected

GOT1L1 (HGNC:28487): (glutamic-oxaloacetic transaminase 1 like 1) Predicted to enable L-aspartate:2-oxoglutarate aminotransferase activity. Predicted to be involved in aspartate biosynthetic process. Predicted to be active in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

GOT1L1 links:

ENSG00000285880 (HGNC:):

ENSG00000285880 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.872

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GOT1L1	NM_152413.3 link	c.884G>A	p.Arg295His	missense_variant	Exon 7 of 9	ENST00000307599.5	NP_689626.2	Q8NHS2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GOT1L1	ENST00000307599.5 link	c.884G>A	p.Arg295His	missense_variant	Exon 7 of 9	1	NM_152413.3	ENSP00000303077.4	Q8NHS2
ENSG00000285880	ENST00000647937.1 link	c.690-534G>A		intron_variant	Intron 1 of 1			ENSP00000497740.1	A0A3B3IT50
GOT1L1	ENST00000518826.3 link	c.215G>A	p.Arg72His	missense_variant	Exon 2 of 3	2		ENSP00000429558.2	E5RI59

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000651

AC:

AN:

245776

Hom.:

AF XY:

0.0000749

AC XY:

AN XY:

133492

show subpopulations

Gnomad AFR exome

AF:

0.0000655

Gnomad AMR exome

AF:

0.0000594

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000661

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000985

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000912

AC:

133

AN:

1458332

Hom.:

Cov.:

AF XY:

0.000102

AC XY:

AN XY:

725320

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.0000226

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000817

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000104

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152296

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000126

Hom.:

Bravo

AF:

0.0000680

ESP6500AA

AF:

0.000243

AC:

ESP6500EA

AF:

0.000119

AC:

ExAC

AF:

0.0000661

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 17, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.884G>A (p.R295H) alteration is located in exon 7 (coding exon 7) of the GOT1L1 gene. This alteration results from a G to A substitution at nucleotide position 884, causing the arginine (R) at amino acid position 295 to be replaced by a histidine (H). 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

0.16

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.75

D;.

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.86

D;D

M_CAP

Pathogenic

0.41

MetaRNN

Pathogenic

0.87

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.2

M;.

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-4.2

D;.

REVEL

Pathogenic

0.78

Sift

Uncertain

0.0070

D;.

Sift4G

Pathogenic

0.0

D;.

Polyphen

1.0

D;.

Vest4

0.86

MVP

0.72

MPC

0.068

ClinPred

0.89

GERP RS

5.1

Varity_R

0.22

gMVP

0.55

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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