21-44143322-C-G

Variant names:

• chr21-44143322-C-G
• rs752956051
• NM_004649.8:c.639C>G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_004649.8(GATD3):​c.639C>G​(p.Ile213Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 0)
• Consequence: GATD3 NM_004649.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.42

Genes affected

GATD3 (HGNC:1273): (glutamine amidotransferase class 1 domain containing 3) This gene encodes a potential mitochondrial protein that is a member of the DJ-1/PfpI gene family. This protein is overexpressed in fetal Down syndrome brain. Alternate splicing results in multiple transcript variants. [provided by RefSeq, May 2010]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.31223196).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GATD3	NM_004649.8	c.639C>G	p.Ile213Met	missense_variant	Exon 6 of 7	ENST00000291577.11	NP_004640.4
GATD3	NM_198155.5	c.546C>G	p.Ile182Met	missense_variant	Exon 5 of 6		NP_937798.4
GATD3	XM_017028479.2	c.381C>G	p.Ile127Met	missense_variant	Exon 5 of 6		XP_016883968.1
GATD3	NR_135220.2	n.601C>G		non_coding_transcript_exon_variant	Exon 5 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GATD3	ENST00000291577.11	c.639C>G	p.Ile213Met	missense_variant	Exon 6 of 7	1	NM_004649.8	ENSP00000291577.6

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD3 exomes AF: 0.0000280 AC: 7 AN: 250054 Hom.: 0 AF XY: 0.0000369 AC XY: 5 AN XY: 135366

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: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000531

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

Alfa AF: 0.0000301 Hom.: 0

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 12, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.639C>G (p.I213M) alteration is located in exon 6 (coding exon 6) of the C21orf33 gene. This alteration results from a C to G substitution at nucleotide position 639, causing the isoleucine (I) at amino acid position 213 to be replaced by a methionine (M). 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	0.32
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	20
DANN	Uncertain	0.99
Eigen	Benign	0.087
Eigen_PC	Benign	0.060
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.31	T;T;T
MetaSVM	Benign	-0.70	T
PROVEAN	Benign	-2.1	N;N;.
REVEL	Benign	0.27
Sift	Benign	0.038	D;D;.
Sift4G	Uncertain	0.035	D;D;.
Vest4		0.64
MVP		0.77
MPC		0.15
ClinPred		0.12	T
GERP RS		2.8
Varity_R		0.17
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

Other links and lift over

dbSNP: rs752956051; hg19: chr21-45563204; COSMIC: COSV105107147; COSMIC: COSV105107147;