Genetic Variant GOT1L1:p.Phe143Cys (chr8-37937368-A-C) – 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.428T>G(p.Phe143Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000414 in 1,450,866 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: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

GOT1L1
NM_152413.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.62

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:

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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, 0.936

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GOT1L1	NM_152413.3 link	c.428T>G	p.Phe143Cys	missense_variant	Exon 4 of 9	ENST00000307599.5	NP_689626.2	Q8NHS2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GOT1L1	ENST00000307599.5 link	c.428T>G	p.Phe143Cys	missense_variant	Exon 4 of 9	1	NM_152413.3	ENSP00000303077.4		Q8NHS2
ENSG00000285880	ENST00000647937.1 link	c.690-2153T>G		intron_variant	Intron 1 of 1			ENSP00000497740.1		A0A3B3IT50

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000212

AC:

AN:

235414

Hom.:

AF XY:

0.0000235

AC XY:

AN XY:

127552

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000285

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000414

AC:

AN:

1450866

Hom.:

Cov.:

AF XY:

0.00000416

AC XY:

AN XY:

721330

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000151

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

Cov.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 18, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.428T>G (p.F143C) alteration is located in exon 4 (coding exon 4) of the GOT1L1 gene. This alteration results from a T to G substitution at nucleotide position 428, causing the phenylalanine (F) at amino acid position 143 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

Uncertain

0.54

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.30

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.60

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.66

M_CAP

Pathogenic

0.45

MetaRNN

Pathogenic

0.94

MetaSVM

Uncertain

0.78

MutationAssessor

Uncertain

2.9

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-7.3

REVEL

Pathogenic

0.85

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.91

MutPred

0.71

Loss of helix (P = 0.3949);

MVP

0.73

MPC

0.067

ClinPred

0.89

GERP RS

5.0

Varity_R

0.77

gMVP

0.76

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