4-38014729-G-C

Variant names:

• chr4-38014729-G-C
• rs59426552
• NM_001396959.1:c.638G>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_001396959.1(TBC1D1):​c.638G>C​(p.Arg213Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R213C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.012 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TBC1D1 NM_001396959.1 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.615
• Publications: 4 publications found

Genes affected

TBC1D1 (HGNC:11578): (TBC1 domain family member 1) TBC1D1 is the founding member of a family of proteins sharing a 180- to 200-amino acid TBC domain presumed to have a role in regulating cell growth and differentiation. These proteins share significant homology with TRE2 (USP6; MIM 604334), yeast Bub2, and CDC16 (MIM 603461) (White et al., 2000 [PubMed 10965142]).[supplied by OMIM, Mar 2008]

TBC1D1 Gene-Disease associations (from GenCC):

• congenital anomaly of kidney and urinary tract

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06325936).
• BP6: Variant 4-38014729-G-C is Benign according to our data. Variant chr4-38014729-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 2345692.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBC1D1	NM_001396959.1	c.638G>C	p.Arg213Pro	missense_variant	Exon 3 of 22	ENST00000698857.1	NP_001383888.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBC1D1	ENST00000698857.1	c.638G>C	p.Arg213Pro	missense_variant	Exon 3 of 22		NM_001396959.1	ENSP00000513987.1

Frequencies

GnomAD3 genomes AF: 0.000352 AC: 49 AN: 139374 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000103

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000141

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000510

Gnomad SAS AF: 0.000535

Gnomad FIN AF: 0.00231

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000283

Gnomad OTH AF: 0.000512

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0118 AC: 6913 AN: 585796 Hom.: 0 Cov.: 29 AF XY: 0.0100 AC XY: 3134 AN XY: 312820

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

African (AFR) AF: 0.00733 AC: 116 AN: 15834

American (AMR) AF: 0.000505 AC: 19 AN: 37600

Ashkenazi Jewish (ASJ) AF: 0.00464 AC: 67 AN: 14446

East Asian (EAS) AF: 0.00369 AC: 72 AN: 19522

South Asian (SAS) AF: 0.00182 AC: 129 AN: 70868

European-Finnish (FIN) AF: 0.00150 AC: 52 AN: 34780

Middle Eastern (MID) AF: 0.00379 AC: 13 AN: 3426

European-Non Finnish (NFE) AF: 0.0170 AC: 6190 AN: 364044

Other (OTH) AF: 0.0101 AC: 255 AN: 25276

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.000351 AC: 49 AN: 139516 Hom.: 0 Cov.: 32 AF XY: 0.000488 AC XY: 33 AN XY: 67658

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

African (AFR) AF: 0.000103 AC: 4 AN: 38868

American (AMR) AF: 0.000141 AC: 2 AN: 14216

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3276

East Asian (EAS) AF: 0.000510 AC: 2 AN: 3920

South Asian (SAS) AF: 0.000532 AC: 2 AN: 3762

European-Finnish (FIN) AF: 0.00231 AC: 20 AN: 8660

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.000283 AC: 18 AN: 63710

Other (OTH) AF: 0.000507 AC: 1 AN: 1974

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Benign:1

Jul 26, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	5.1
DANN	Benign	0.69
DEOGEN2	Benign	0.061	.;T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.59	T;T;T
M_CAP	Benign	0.0097	T
MetaRNN	Benign	0.063	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N;.
PhyloP100		0.61
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.14	N;N;N
REVEL	Benign	0.028
Sift	Benign	0.27	T;T;T
Sift4G	Benign	0.27	T;T;T
Polyphen		0.0	.;B;.
Vest4		0.067
MutPred		0.25		Loss of glycosylation at P216 (P = 0.0095);Loss of glycosylation at P216 (P = 0.0095);.;
MVP		0.16
MPC		0.76
ClinPred		0.081	T
GERP RS		-0.059
Varity_R		0.079
gMVP		0.31
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs59426552; hg19: chr4-38016350;