TBC1D1 p.Ser14Pro

Variant names:

• chr4-37902135-T-C
• rs2279027
• NM_001396959.1:c.40T>C
• TBC1D1 p.Ser14Pro

Your query was ambiguous. Multiple possible variants found:

• chr4-37902135-T-C
• chr4-37902135-TCT-CCC
• chr4-37902135-TCT-CCA
• chr4-37902135-TCT-CCG

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001396959.1(TBC1D1):​c.40T>C​(p.Ser14Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.607 in 1,610,302 control chromosomes in the GnomAD database, including 299,968 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.67 (34650 hom., cov: 29)
  • Exomes 𝑓: 0.60 (265318 hom.)
• Consequence: TBC1D1 NM_001396959.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.247
• Publications: 37 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):

• non-syndromic renal or urinary tract malformation

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• congenital anomaly of kidney and urinary tract

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.2453226E-7).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.832 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001396959.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBC1D1	NM_001396959.1	MANE Select	c.40T>C	p.Ser14Pro	missense	Exon 2 of 22	NP_001383888.1	A0A8V8TNS9
	TBC1D1	NM_015173.4		c.40T>C	p.Ser14Pro	missense	Exon 2 of 20	NP_055988.2
	TBC1D1	NM_001253912.2		c.40T>C	p.Ser14Pro	missense	Exon 2 of 21	NP_001240841.1	Q86TI0-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBC1D1	ENST00000698857.1	MANE Select	c.40T>C	p.Ser14Pro	missense	Exon 2 of 22	ENSP00000513987.1	A0A8V8TNS9
	TBC1D1	ENST00000261439.9	TSL:1	c.40T>C	p.Ser14Pro	missense	Exon 2 of 20	ENSP00000261439.4	Q86TI0-1
	TBC1D1	ENST00000961338.1		c.40T>C	p.Ser14Pro	missense	Exon 2 of 23	ENSP00000631397.1

Frequencies

GnomAD3 genomes AF: 0.668 AC: 101261 AN: 151694 Hom.: 34592 Cov.: 29

Gnomad AFR AF: 0.838

Gnomad AMI AF: 0.618

Gnomad AMR AF: 0.608

Gnomad ASJ AF: 0.557

Gnomad EAS AF: 0.631

Gnomad SAS AF: 0.636

Gnomad FIN AF: 0.687

Gnomad MID AF: 0.563

Gnomad NFE AF: 0.586

Gnomad OTH AF: 0.648

GnomAD2 exomes AF: 0.618 AC: 153187 AN: 248024 AF XY: 0.614

Gnomad AFR exome AF: 0.846

Gnomad AMR exome AF: 0.541

Gnomad ASJ exome AF: 0.559

Gnomad EAS exome AF: 0.647

Gnomad FIN exome AF: 0.684

Gnomad NFE exome AF: 0.591

Gnomad OTH exome AF: 0.620

GnomAD4 exome AF: 0.601 AC: 875856 AN: 1458490 Hom.: 265318 Cov.: 61 AF XY: 0.600 AC XY: 435407 AN XY: 725742

African (AFR) AF: 0.843 AC: 28041 AN: 33256

American (AMR) AF: 0.549 AC: 24018 AN: 43730

Ashkenazi Jewish (ASJ) AF: 0.566 AC: 14607 AN: 25822

East Asian (EAS) AF: 0.652 AC: 25856 AN: 39678

South Asian (SAS) AF: 0.627 AC: 54040 AN: 86140

European-Finnish (FIN) AF: 0.679 AC: 36217 AN: 53352

Middle Eastern (MID) AF: 0.573 AC: 3283 AN: 5728

European-Non Finnish (NFE) AF: 0.588 AC: 653259 AN: 1110618

Other (OTH) AF: 0.607 AC: 36535 AN: 60166

GnomAD4 genome AF: 0.668 AC: 101363 AN: 151812 Hom.: 34650 Cov.: 29 AF XY: 0.670 AC XY: 49680 AN XY: 74190

African (AFR) AF: 0.839 AC: 34732 AN: 41400

American (AMR) AF: 0.607 AC: 9252 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.557 AC: 1934 AN: 3470

East Asian (EAS) AF: 0.632 AC: 3254 AN: 5152

South Asian (SAS) AF: 0.634 AC: 3031 AN: 4778

European-Finnish (FIN) AF: 0.687 AC: 7234 AN: 10524

Middle Eastern (MID) AF: 0.585 AC: 172 AN: 294

European-Non Finnish (NFE) AF: 0.586 AC: 39825 AN: 67922

Other (OTH) AF: 0.648 AC: 1367 AN: 2108

Alfa AF: 0.611 Hom.: 97763

Bravo AF: 0.668

Asia WGS AF: 0.671 AC: 2335 AN: 3478

EpiCase AF: 0.582

EpiControl AF: 0.587

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.043
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	11
DANN	Benign	0.082
DEOGEN2	Benign	0.019	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0018	N
LIST_S2	Benign	0.37	T
MetaRNN	Benign	8.2e-7	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.8	N
PhyloP100		0.25
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.85	N
REVEL	Benign	0.094
Sift	Benign	1.0	T
Sift4G	Benign	0.49	T
Varity_R		0.044
gMVP		0.27
Mutation Taster		=99/1	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2279027;

hg19: chr4-37903756;

COSMIC: COSV54722928;