chr4-37902135-T-C

Position:

• chr4-37902135-T-C

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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

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]

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TBC1D1	NM_001396959.1	c.40T>C	p.Ser14Pro	missense_variant	2/22	ENST00000698857.1	NP_001383888.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TBC1D1	ENST00000698857.1	c.40T>C	p.Ser14Pro	missense_variant	2/22		NM_001396959.1	ENSP00000513987	A2
TBC1D1	ENST00000261439.9	c.40T>C	p.Ser14Pro	missense_variant	2/20	1		ENSP00000261439	P2
TBC1D1	ENST00000508802.5	c.40T>C	p.Ser14Pro	missense_variant	2/21	2		ENSP00000423651
TBC1D1	ENST00000402522.1	c.40T>C	p.Ser14Pro	missense_variant	2/3	2		ENSP00000383994

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

GnomAD3 exomes AF: 0.618 AC: 153187 AN: 248024 Hom.: 48116 AF XY: 0.614 AC XY: 82433 AN XY: 134248

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 SAS exome AF: 0.634

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

Gnomad4 AFR exome AF: 0.843

Gnomad4 AMR exome AF: 0.549

Gnomad4 ASJ exome AF: 0.566

Gnomad4 EAS exome AF: 0.652

Gnomad4 SAS exome AF: 0.627

Gnomad4 FIN exome AF: 0.679

Gnomad4 NFE exome AF: 0.588

Gnomad4 OTH exome AF: 0.607

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

Gnomad4 AFR AF: 0.839

Gnomad4 AMR AF: 0.607

Gnomad4 ASJ AF: 0.557

Gnomad4 EAS AF: 0.632

Gnomad4 SAS AF: 0.634

Gnomad4 FIN AF: 0.687

Gnomad4 NFE AF: 0.586

Gnomad4 OTH AF: 0.648

Alfa AF: 0.599 Hom.: 68157

Bravo AF: 0.668

TwinsUK AF: 0.587 AC: 2176

ALSPAC AF: 0.581 AC: 2241

ESP6500AA AF: 0.836 AC: 3684

ESP6500EA AF: 0.594 AC: 5112

ExAC AF: 0.623 AC: 75584

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 v4.3

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;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0018	N
LIST_S2	Benign	0.37	T;T;T
MetaRNN	Benign	8.2e-7	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.8	N;N;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.85	N;N;N
REVEL	Benign	0.094
Sift	Benign	1.0	T;T;T
Sift4G	Benign	0.49	T;T;T
Polyphen		0.0	.;B;.
Vest4		0.049
MPC		0.66
ClinPred		0.0010	T
GERP RS		4.9
Varity_R		0.044
gMVP		0.27

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

Publications

LitVar

Other links and lift over

dbSNP: rs2279027; hg19: chr4-37903756; COSMIC: COSV54722928;