12-110647241-A-T

Variant names:

• chr12-110647241-A-T
• rs371539069
• NM_001082538.3:c.1540A>T

Variant summary

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

The NM_001082538.3(TCTN1):​c.1540A>T​(p.Ile514Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. I514V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TCTN1 NM_001082538.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.976
• Publications: 0 publications found

Genes affected

TCTN1 (HGNC:26113): (tectonic family member 1) This gene encodes a member of a family of secreted and transmembrane proteins. The orthologous gene in mouse functions downstream of smoothened and rab23 to modulate hedgehog signal transduction. This protein is a component of the tectonic-like complex, which forms a barrier between the ciliary axoneme and the basal body. A mutation in this gene was found in a family with Joubert syndrome-13. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

HVCN1 (HGNC:28240): (hydrogen voltage gated channel 1) This gene encodes a voltage-gated protein channel protein expressed more highly in certain cells of the immune system. Phagocytic cells produce superoxide anions which require this channel protein, and in B cells this same process facilitates antibody production. This same channel protein, however, can also regulate functions in other cells including spermatozoa. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]

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=0.15121529).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCTN1	NM_001082538.3	c.1540A>T	p.Ile514Leu	missense_variant	Exon 13 of 15	ENST00000397659.9	NP_001076007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCTN1	ENST00000397659.9	c.1540A>T	p.Ile514Leu	missense_variant	Exon 13 of 15	1	NM_001082538.3	ENSP00000380779.4
TCTN1	ENST00000551590.5	c.1525A>T	p.Ile509Leu	missense_variant	Exon 13 of 15	1		ENSP00000448735.1
TCTN1	ENST00000397655.7	c.1483A>T	p.Ile495Leu	missense_variant	Exon 13 of 15	1		ENSP00000380775.3
TCTN1	ENST00000397656.8	n.*1158A>T		non_coding_transcript_exon_variant	Exon 14 of 16	2		ENSP00000380776.4
TCTN1	ENST00000480648.5	n.*801A>T		non_coding_transcript_exon_variant	Exon 14 of 16	5		ENSP00000437196.1
TCTN1	ENST00000495659.6	n.*1283A>T		non_coding_transcript_exon_variant	Exon 13 of 15	2		ENSP00000436673.2
TCTN1	ENST00000397656.8	n.*1158A>T		3_prime_UTR_variant	Exon 14 of 16	2		ENSP00000380776.4
TCTN1	ENST00000480648.5	n.*801A>T		3_prime_UTR_variant	Exon 14 of 16	5		ENSP00000437196.1
TCTN1	ENST00000495659.6	n.*1283A>T		3_prime_UTR_variant	Exon 13 of 15	2		ENSP00000436673.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.042	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	13
DANN	Benign	0.81
DEOGEN2	Benign	0.14	.;T;.;.;.
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.75	T;T;T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.15	T;T;T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.7	.;L;.;.;.
PhyloP100		0.98
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.1	.;N;N;N;.
REVEL	Benign	0.16
Sift	Benign	0.30	.;T;T;T;.
Sift4G	Benign	0.57	T;T;T;T;T
Polyphen		0.010, 0.10	.;B;B;B;.
Vest4		0.32
MutPred		0.59		.;Gain of catalytic residue at V508 (P = 0.0019);.;.;.;
MVP		0.62
MPC		0.21
ClinPred		0.12	T
GERP RS		0.84
Varity_R		0.043
gMVP		0.48
Mutation Taster		=88/12	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: rs371539069; hg19: chr12-111085046;