chr22-50197890-G-A

Position:

• chr22-50197890-G-A

Variant summary

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

The NM_001320485.2(TRABD):​c.739G>A​(p.Glu247Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,914 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: TRABD NM_001320485.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.50

Genes affected

TRABD (HGNC:28805): (TraB domain containing)

TRABD (HGNC:):

ACMG classification

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/exons	MANE	Protein	UniProt
TRABD	NM_001320485.2	c.739G>A	p.Glu247Lys	missense_variant	8/10	ENST00000380909.9	NP_001307414.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRABD	ENST00000380909.9	c.739G>A	p.Glu247Lys	missense_variant	8/10	5	NM_001320485.2	ENSP00000370295.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000802 AC: 2 AN: 249456 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135268

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 0.00000893

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460914 Hom.: 0 Cov.: 37 AF XY: 0.00000275 AC XY: 2 AN XY: 726772

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

Bravo AF: 0.0000151

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 01, 2023

The c.739G>A (p.E247K) alteration is located in exon 8 (coding exon 7) of the TRABD gene. This alteration results from a G to A substitution at nucleotide position 739, causing the glutamic acid (E) at amino acid position 247 to be replaced by a lysine (K). 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	0.50
BayesDel_addAF	Uncertain	0.048	T
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.22	T;T;T;T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	.;.;D;D
M_CAP	Benign	0.081	D
MetaRNN	Uncertain	0.71	D;D;D;D
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.2	M;M;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.5	D;D;D;D
REVEL	Uncertain	0.31
Sift	Uncertain	0.019	D;D;D;D
Sift4G	Uncertain	0.0090	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.85
MutPred		0.62		Gain of methylation at E247 (P = 0.0075);Gain of methylation at E247 (P = 0.0075);Gain of methylation at E247 (P = 0.0075);Gain of methylation at E247 (P = 0.0075);
MVP		0.24
MPC		0.71
ClinPred		0.94	D
GERP RS		4.1
Varity_R		0.64
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs746954295; hg19: chr22-50636319;