Genetic Variant GOT1L1:p.Arg127Cys (chr8-37937668-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_152413.3(GOT1L1):c.379C>T(p.Arg127Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000335 in 1,612,058 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

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

Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

GOT1L1
NM_152413.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0210

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GOT1L1	NM_152413.3 link	c.379C>T	p.Arg127Cys	missense_variant	Exon 3 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.379C>T	p.Arg127Cys	missense_variant	Exon 3 of 9	1	NM_152413.3	ENSP00000303077.4	Q8NHS2
ENSG00000285880	ENST00000647937.1 link	c.690-2453C>T		intron_variant	Intron 1 of 1			ENSP00000497740.1	A0A3B3IT50
GOT1L1	ENST00000524298.1 link	c.475C>T	p.Arg159Cys	missense_variant	Exon 3 of 3	3		ENSP00000430453.1	E5RJX9

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152012

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000962

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

GnomAD3 exomes

AF:

0.0000365

AC:

AN:

246580

Hom.:

AF XY:

0.0000299

AC XY:

AN XY:

133704

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000336

Gnomad SAS exome

AF:

0.0000331

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000179

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000315

AC:

AN:

1459928

Hom.:

Cov.:

AF XY:

0.0000331

AC XY:

AN XY:

726116

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000176

Gnomad4 SAS exome

AF:

0.0000233

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000810

Gnomad4 OTH exome

AF:

0.000315

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152130

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000965

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000113

Hom.:

Bravo

AF:

0.0000869

ExAC

AF:

0.0000414

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 19, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.379C>T (p.R127C) alteration is located in exon 3 (coding exon 3) of the GOT1L1 gene. This alteration results from a C to T substitution at nucleotide position 379, causing the arginine (R) at amino acid position 127 to be replaced by a cysteine (C). 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

-0.34

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.42

T;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.067

LIST_S2

Benign

0.56

T;T

M_CAP

Benign

0.010

MetaRNN

Benign

0.026

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.4

M;.

PrimateAI

Benign

0.20

PROVEAN

Benign

-2.1

N;D

REVEL

Benign

0.16

Sift

Uncertain

0.016

D;D

Sift4G

Uncertain

0.031

D;.

Polyphen

0.99

D;.

Vest4

0.26

MutPred

0.43

Loss of MoRF binding (P = 6e-04);.;

MVP

0.15

MPC

0.039

ClinPred

0.11

GERP RS

-2.8

Varity_R

0.082

gMVP

0.40

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.22

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.22

Position offset: -30

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