4-37902351-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001396959.1(TBC1D1):c.256G>C(p.Asp86His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000157 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D86Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: TBC1D1 NM_001396959.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.75

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBC1D1	NM_001396959.1	c.256G>C	p.Asp86His	missense_variant	2/22	ENST00000698857.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBC1D1	ENST00000698857.1	c.256G>C	p.Asp86His	missense_variant	2/22		NM_001396959.1	A2
TBC1D1	ENST00000261439.9	c.256G>C	p.Asp86His	missense_variant	2/20	1		P2
TBC1D1	ENST00000508802.5	c.256G>C	p.Asp86His	missense_variant	2/21	2
TBC1D1	ENST00000402522.1	c.256G>C	p.Asp86His	missense_variant	2/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000157 AC: 23 AN: 1461888 Hom.: 0 Cov.: 36 AF XY: 0.0000138 AC XY: 10 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 06, 2023

The c.256G>C (p.D86H) alteration is located in exon 2 (coding exon 1) of the TBC1D1 gene. This alteration results from a G to C substitution at nucleotide position 256, causing the aspartic acid (D) at amino acid position 86 to be replaced by a histidine (H). 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	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
Cadd	Pathogenic	26
Dann	Uncertain	1.0
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.56	D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.3	N;N;D
REVEL	Benign	0.27
Sift	Uncertain	0.0090	D;D;D
Sift4G	Uncertain	0.019	D;D;D
Polyphen		0.29	.;B;.
Vest4		0.71
MutPred		0.26		Gain of glycosylation at Y90 (P = 0.0107);Gain of glycosylation at Y90 (P = 0.0107);Gain of glycosylation at Y90 (P = 0.0107);
MVP		0.56
MPC		1.6
ClinPred		0.95	D
GERP RS		6.1
Varity_R		0.064
gMVP		0.64

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: rs746844362; hg19: chr4-37903972;