4-26620649-A-C

Variant names:

• chr4-26620649-A-C
• rs1382424174
• NM_018317.4:c.255A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018317.4(TBC1D19):​c.255A>C​(p.Glu85Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000868 in 1,613,640 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: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: TBC1D19 NM_018317.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.378
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25146097).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBC1D19	NM_018317.4	c.255A>C	p.Glu85Asp	missense_variant	Exon 4 of 21	ENST00000264866.9	NP_060787.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBC1D19	ENST00000264866.9	c.255A>C	p.Glu85Asp	missense_variant	Exon 4 of 21	1	NM_018317.4	ENSP00000264866.4

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152134 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251010 AF XY: 0.00

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 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: 1461506 Hom.: 0 Cov.: 30 AF XY: 0.00000963 AC XY: 7 AN XY: 727054

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39628

South Asian (SAS) AF: 0.00 AC: 0 AN: 86198

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

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

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1111864

Other (OTH) AF: 0.00 AC: 0 AN: 60372

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152134 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74290

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

African (AFR) AF: 0.00 AC: 0 AN: 41428

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2086

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.002339), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 21, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.255A>C (p.E85D) alteration is located in exon 4 (coding exon 4) of the TBC1D19 gene. This alteration results from a A to C substitution at nucleotide position 255, causing the glutamic acid (E) at amino acid position 85 to be replaced by an aspartic acid (D). 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	0.26
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.018	.;.;T;.
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.25	T;T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.3	.;.;M;.
PhyloP100		0.38
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.5	N;N;N;N
REVEL	Benign	0.25
Sift	Pathogenic	0.0	D;T;T;T
Sift4G	Pathogenic	0.0	D;T;T;T
Polyphen		0.95	.;.;P;.
Vest4		0.51
MutPred		0.17		.;.;Loss of helix (P = 0.0626);.;
MVP		0.45
MPC		0.85
ClinPred		0.92	D
GERP RS		-5.7
Varity_R		0.16
gMVP		0.28
Mutation Taster		=76/24	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1382424174; hg19: chr4-26622271;