6-13364769-G-A

Variant names:

• chr6-13364769-G-A
• rs1410588815
• NM_018988.4:c.1147C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_018988.4(GFOD1):​c.1147C>T​(p.Arg383Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,460,802 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: GFOD1 NM_018988.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.42

Genes affected

GFOD1 (HGNC:21096): (Gfo/Idh/MocA-like oxidoreductase domain containing 1) Predicted to enable nucleotide binding activity and oxidoreductase activity. Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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=0.2849141).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFOD1	NM_018988.4	c.1147C>T	p.Arg383Cys	missense_variant	Exon 2 of 2	ENST00000379287.4	NP_061861.1
GFOD1	NM_001242628.2	c.838C>T	p.Arg280Cys	missense_variant	Exon 2 of 2		NP_001229557.1
GFOD1	NM_001242630.2	c.838C>T	p.Arg280Cys	missense_variant	Exon 2 of 2		NP_001229559.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GFOD1	ENST00000379287.4	c.1147C>T	p.Arg383Cys	missense_variant	Exon 2 of 2	1	NM_018988.4	ENSP00000368589.3
GFOD1	ENST00000379284.1	c.838C>T	p.Arg280Cys	missense_variant	Exon 2 of 2	2		ENSP00000368586.1
GFOD1	ENST00000612338.4	c.838C>T	p.Arg280Cys	missense_variant	Exon 2 of 2	2		ENSP00000479493.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250604 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135564

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1460802 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 726628

Gnomad4 AFR exome AF: 0.00

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: 0.0000108

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 12, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1147C>T (p.R383C) alteration is located in exon 2 (coding exon 2) of the GFOD1 gene. This alteration results from a C to T substitution at nucleotide position 1147, causing the arginine (R) at amino acid position 383 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	0.43
BayesDel_addAF	Uncertain	0.076	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.071	.;T;.
Eigen	Benign	0.13
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.95	.;D;D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.28	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	.;M;.
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-1.9	N;N;.
REVEL	Benign	0.18
Sift	Uncertain	0.0030	D;D;.
Sift4G	Uncertain	0.0030	D;T;D
Polyphen		1.0	.;D;.
Vest4		0.44
MutPred		0.34		.;Gain of catalytic residue at M381 (P = 5e-04);.;
MVP		0.72
MPC		2.1
ClinPred		0.74	D
GERP RS		1.8
Varity_R		0.18
gMVP		0.85

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

Other links and lift over

dbSNP: rs1410588815; hg19: chr6-13365001; COSMIC: COSV64954500;