17-59890897-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016261.4(TUBD1):c.106A>G(p.Met36Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 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. M36L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: TUBD1 NM_016261.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.89

Genes affected

TUBD1 (HGNC:16811): (tubulin delta 1) Predicted to enable GTP binding activity. Predicted to be a structural constituent of cytoskeleton. Predicted to be involved in microtubule cytoskeleton organization; mitotic cell cycle; and positive regulation of smoothened signaling pathway. Located in cytosol and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.117955595).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TUBD1	NM_016261.4	c.106A>G	p.Met36Val	missense_variant	2/9	ENST00000325752.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TUBD1	ENST00000325752.8	c.106A>G	p.Met36Val	missense_variant	2/9	5	NM_016261.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 251046 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135730

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461646 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727138

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000672

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2022

The c.106A>G (p.M36V) alteration is located in exon 2 (coding exon 1) of the TUBD1 gene. This alteration results from a A to G substitution at nucleotide position 106, causing the methionine (M) at amino acid position 36 to be replaced by a valine (V). 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	Benign	0.068
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	18
Dann	Benign	0.93
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.068
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.45	T;T;T;T;T;.;.;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.12	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.57	N;N;N;N;N;N;N;.
MutationTaster	Benign	1.0	D;N;N;N;N;N;N
PrimateAI	Uncertain	0.49	T
Sift4G	Benign	0.51	T;T;T;T;T;T;T;.
Polyphen		0.0, 0.0040	.;B;B;B;.;.;B;.
Vest4		0.15
MutPred		0.55		Loss of disorder (P = 0.1034);Loss of disorder (P = 0.1034);Loss of disorder (P = 0.1034);Loss of disorder (P = 0.1034);Loss of disorder (P = 0.1034);Loss of disorder (P = 0.1034);Loss of disorder (P = 0.1034);.;
MVP		0.71
MPC		0.11
ClinPred		0.11	T
GERP RS		4.7
Varity_R		0.050
gMVP		0.32

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

Publications

LitVar

Other links and lift over

dbSNP: rs758436504; hg19: chr17-57968258;