chr10-95693689-C-G

Variant names:

• chr10-95693689-C-G
• rs138495428
• NM_015631.6:c.211G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015631.6(TCTN3):​c.211G>C​(p.Val71Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,399,396 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: TCTN3 NM_015631.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0140
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• orofaciodigital syndrome IV

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Laboratory for Molecular Medicine
• Joubert syndrome 18

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Meckel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• orofaciodigital syndrome type 6

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10034993).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCTN3	NM_015631.6	c.211G>C	p.Val71Leu	missense_variant	Exon 1 of 14	ENST00000371217.10	NP_056446.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCTN3	ENST00000371217.10	c.211G>C	p.Val71Leu	missense_variant	Exon 1 of 14	1	NM_015631.6	ENSP00000360261.5
TCTN3	ENST00000265993.13	c.265G>C	p.Val89Leu	missense_variant	Exon 1 of 14	1		ENSP00000265993.9
TCTN3	ENST00000430368.6	c.211G>C	p.Val71Leu	missense_variant	Exon 1 of 10	2		ENSP00000387567.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1399396 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 690198

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31598

American (AMR) AF: 0.00 AC: 0 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25172

East Asian (EAS) AF: 0.00 AC: 0 AN: 35738

South Asian (SAS) AF: 0.00 AC: 0 AN: 79236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49278

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1078972

Other (OTH) AF: 0.00 AC: 0 AN: 58000

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	13
DANN	Benign	0.92
DEOGEN2	Benign	0.0088	T;T;.;.;.
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.0083	N
LIST_S2	Benign	0.66	T;.;T;T;T
M_CAP	Uncertain	0.086	D
MetaRNN	Benign	0.10	T;T;T;T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.8	L;L;.;L;L
PhyloP100		-0.014
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.33	.;.;.;N;N
REVEL	Benign	0.17
Sift	Benign	0.19	.;.;.;T;T
Sift4G	Benign	0.38	T;T;T;T;T
Polyphen		0.66	P;P;.;.;P
Vest4		0.037
MutPred		0.23		Loss of sheet (P = 0.0104);Loss of sheet (P = 0.0104);.;Loss of sheet (P = 0.0104);Loss of sheet (P = 0.0104);
MVP		0.83
MPC		0.11
ClinPred		0.12	T
GERP RS		2.1
PromoterAI		-0.099	Neutral
Varity_R		0.055
gMVP		0.32
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs138495428; hg19: chr10-97453446;