4-37902458-C-T

Variant names:

• chr4-37902458-C-T
• rs145529203
• NM_001396959.1:c.363C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001396959.1(TBC1D1):​c.363C>T​(p.Asp121Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00172 in 1,613,840 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (4 hom.)
• Consequence: TBC1D1 NM_001396959.1 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0400
• Publications: 2 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: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 4-37902458-C-T is Benign according to our data. Variant chr4-37902458-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 711939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.04 with no splicing effect.
• BS2: High AC in GnomAd4 at 172 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBC1D1	NM_001396959.1	c.363C>T	p.Asp121Asp	synonymous_variant	Exon 2 of 22	ENST00000698857.1	NP_001383888.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBC1D1	ENST00000698857.1	c.363C>T	p.Asp121Asp	synonymous_variant	Exon 2 of 22		NM_001396959.1	ENSP00000513987.1
TBC1D1	ENST00000261439.9	c.363C>T	p.Asp121Asp	synonymous_variant	Exon 2 of 20	1		ENSP00000261439.4
TBC1D1	ENST00000508802.5	c.363C>T	p.Asp121Asp	synonymous_variant	Exon 2 of 21	2		ENSP00000423651.1
TBC1D1	ENST00000402522.1	c.363C>T	p.Asp121Asp	synonymous_variant	Exon 2 of 3	2		ENSP00000383994.1

Frequencies

GnomAD3 genomes AF: 0.00113 AC: 172 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00197

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00118 AC: 297 AN: 251090 AF XY: 0.00127

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000278

Gnomad NFE exome AF: 0.00179

Gnomad OTH exome AF: 0.000981

GnomAD4 exome AF: 0.00178 AC: 2596 AN: 1461578 Hom.: 4 Cov.: 36 AF XY: 0.00172 AC XY: 1249 AN XY: 727072

African (AFR) AF: 0.000358 AC: 12 AN: 33480

American (AMR) AF: 0.00121 AC: 54 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000777 AC: 67 AN: 86196

European-Finnish (FIN) AF: 0.000262 AC: 14 AN: 53402

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.00211 AC: 2347 AN: 1111848

Other (OTH) AF: 0.00159 AC: 96 AN: 60384

GnomAD4 genome AF: 0.00113 AC: 172 AN: 152262 Hom.: 0 Cov.: 32 AF XY: 0.00109 AC XY: 81 AN XY: 74452

African (AFR) AF: 0.000385 AC: 16 AN: 41558

American (AMR) AF: 0.000654 AC: 10 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4822

European-Finnish (FIN) AF: 0.0000944 AC: 1 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00197 AC: 134 AN: 68012

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00186 Hom.: 1

Bravo AF: 0.00126

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00180

EpiControl AF: 0.00225

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TBC1D1: BP4, BP7 -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	4.2
DANN	Benign	0.34
PhyloP100		-0.040
Mutation Taster		=100/0	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: rs145529203; hg19: chr4-37904079; COSMIC: COSV54715618;