4-26673826-A-T

Variant names:

• chr4-26673826-A-T
• rs372797439
• NM_018317.4:c.754A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018317.4(TBC1D19):​c.754A>T​(p.Ser252Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,314 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S252G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TBC1D19 NM_018317.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.74
• Publications: 0 publications found

Genes affected

TBC1D19 (HGNC:25624): (TBC1 domain family member 19) Predicted to enable GTPase activator activity. Predicted to be involved in regulation of catalytic activity. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.039496392).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBC1D19	NM_018317.4	c.754A>T	p.Ser252Cys	missense_variant	Exon 11 of 21	ENST00000264866.9	NP_060787.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBC1D19	ENST00000264866.9	c.754A>T	p.Ser252Cys	missense_variant	Exon 11 of 21	1	NM_018317.4	ENSP00000264866.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459314 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 725992

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33360

American (AMR) AF: 0.00 AC: 0 AN: 44612

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26076

East Asian (EAS) AF: 0.00 AC: 0 AN: 39558

South Asian (SAS) AF: 0.00 AC: 0 AN: 86042

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53332

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1110316

Other (OTH) AF: 0.00 AC: 0 AN: 60254

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	18
DANN	Benign	0.062
DEOGEN2	Benign	0.015	.;T;.;.
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.88	D;D;D;D
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.039	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.8	.;N;.;.
PhyloP100		4.7
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	4.6	N;N;N;N
REVEL	Benign	0.14
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0	.;B;.;.
Vest4		0.20, 0.20
MutPred		0.45		.;Loss of disorder (P = 0.011);.;.;
MVP		0.49
MPC		0.29
ClinPred		0.48	T
GERP RS		5.2
Varity_R		0.13
gMVP		0.41
Mutation Taster		=79/21	polymorphism

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

Other links and lift over

dbSNP: rs372797439; hg19: chr4-26675448;