10-95683128-A-G

Position:

• chr10-95683128-A-G

Variant summary

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

The NM_015631.6(TCTN3):​c.1271T>C​(p.Val424Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,770 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/20 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: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TCTN3 NM_015631.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.03

Genes affected

TCTN3 (HGNC:24519): (tectonic family member 3) This gene encodes a member of the tectonic gene family which functions in Hedgehog signal transduction and development of the neural tube. Mutations in this gene have been associated with Orofaciodigital Syndrome IV and Joubert Syndrom 18. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Sep 2012]

TCTN3 (HGNC:):

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	Protein	UniProt
TCTN3	NM_015631.6	c.1271T>C	p.Val424Ala	missense_variant	11/14	ENST00000371217.10	NP_056446.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCTN3	ENST00000371217.10	c.1271T>C	p.Val424Ala	missense_variant	11/14	1	NM_015631.6	ENSP00000360261.5
TCTN3	ENST00000265993.13	c.1325T>C	p.Val442Ala	missense_variant	11/14	1		ENSP00000265993.9
TCTN3	ENST00000430368.6	c.827T>C	p.Val276Ala	missense_variant	7/10	2		ENSP00000387567.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251396 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135854

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 6.84e-7 AC: 1 AN: 1461770 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727180

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.024	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.019	T;T;.;.
Eigen	Benign	0.067
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.75	T;.;T;T
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.47	T;T;T;T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Uncertain	2.7	M;M;.;.
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.5	.;.;.;N
REVEL	Uncertain	0.47
Sift	Benign	0.15	.;.;.;T
Sift4G	Benign	0.32	T;T;T;T
Polyphen		0.26	B;B;.;.
Vest4		0.54
MutPred		0.61		Gain of loop (P = 0.069);Gain of loop (P = 0.069);.;.;
MVP		0.39
MPC		0.17
ClinPred		0.40	T
GERP RS		5.4
Varity_R		0.079
gMVP		0.35

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: rs200705429; hg19: chr10-97442885;