rs41291570

chr10-95693676-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015631.6(TCTN3):c.224C>T(p.Ala75Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00627 in 1,551,710 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A75T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0045 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0065 (61 hom.)
• Consequence: TCTN3 NM_015631.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.271

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00509724).
• BP6: Variant 10-95693676-G-A is Benign according to our data. Variant chr10-95693676-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 212392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-95693676-G-A is described in Lovd as [Benign]. Variant chr10-95693676-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00452 (688/152324) while in subpopulation SAS AF= 0.0133 (64/4826). AF 95% confidence interval is 0.0107. There are 2 homozygotes in gnomad4. There are 317 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCTN3	NM_015631.6	c.224C>T	p.Ala75Val	missense_variant	1/14	ENST00000371217.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCTN3	ENST00000371217.10	c.224C>T	p.Ala75Val	missense_variant	1/14	1	NM_015631.6	P2

Frequencies

GnomAD3 genomes AF: 0.00455 AC: 692 AN: 152206 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00154

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.00294

Gnomad ASJ AF: 0.00691

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0135

Gnomad FIN AF: 0.00556

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00592

Gnomad OTH AF: 0.00623

GnomAD3 exomes AF: 0.00717 AC: 1119 AN: 156070 Hom.: 10 AF XY: 0.00786 AC XY: 651 AN XY: 82784

Gnomad AFR exome AF: 0.00101

Gnomad AMR exome AF: 0.00377

Gnomad ASJ exome AF: 0.0112

Gnomad EAS exome AF: 0.0000918

Gnomad SAS exome AF: 0.0150

Gnomad FIN exome AF: 0.00928

Gnomad NFE exome AF: 0.00640

Gnomad OTH exome AF: 0.00912

GnomAD4 exome AF: 0.00646 AC: 9035 AN: 1399386 Hom.: 61 Cov.: 32 AF XY: 0.00672 AC XY: 4638 AN XY: 690200

Gnomad4 AFR exome AF: 0.00206

Gnomad4 AMR exome AF: 0.00378

Gnomad4 ASJ exome AF: 0.00998

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.0151

Gnomad4 FIN exome AF: 0.00974

Gnomad4 NFE exome AF: 0.00593

Gnomad4 OTH exome AF: 0.00729

GnomAD4 genome AF: 0.00452 AC: 688 AN: 152324 Hom.: 2 Cov.: 33 AF XY: 0.00426 AC XY: 317 AN XY: 74490

Gnomad4 AFR AF: 0.00154

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.00691

Gnomad4 EAS AF: 0.000771

Gnomad4 SAS AF: 0.0133

Gnomad4 FIN AF: 0.00556

Gnomad4 NFE AF: 0.00591

Gnomad4 OTH AF: 0.00569

Alfa AF: 0.00545 Hom.: 1

Bravo AF: 0.00416

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.00289 AC: 4

ESP6500EA AF: 0.00597 AC: 19

ExAC AF: 0.00901 AC: 224

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 15, 2015	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 07, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 28, 2016	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	TCTN3: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Orofacial-digital syndrome IV;C3553758:Joubert syndrome 18 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	12
Dann	Uncertain	0.98
DEOGEN2	Benign	0.0038	T;T;.;.;.
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.0059	N
LIST_S2	Benign	0.70	T;.;T;T;T
MetaRNN	Benign	0.0051	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;L;.;L;L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.29	T
Sift4G	Benign	0.28	T;T;T;T;T
Polyphen		0.0020	B;B;.;.;B
Vest4		0.020
MVP		0.85
MPC		0.11
ClinPred		0.0019	T
GERP RS		-0.71
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.028
gMVP		0.28

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: rs41291570; hg19: chr10-97453433; COSMIC: COSV105061077;