rs41291570

Variant names:

• chr10-95693676-G-A
• rs41291570
• NM_015631.6:c.224C>T

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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:9
• Conservation: PhyloP100: 0.271
• Publications: 6 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: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Orphanet, G2P, PanelApp Australia
• Joubert syndrome 18

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

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 212392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015631.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCTN3	NM_015631.6	MANE Select	c.224C>T	p.Ala75Val	missense	Exon 1 of 14	NP_056446.4	Q6NUS6-1
	TCTN3	NM_001410982.1		c.224C>T	p.Ala75Val	missense	Exon 1 of 13	NP_001397911.1	A0A7P0TB57
	TCTN3	NM_001143973.2		c.224C>T	p.Ala75Val	missense	Exon 1 of 10	NP_001137445.1	Q6NUS6-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCTN3	ENST00000371217.10	TSL:1 MANE Select	c.224C>T	p.Ala75Val	missense	Exon 1 of 14	ENSP00000360261.5	Q6NUS6-1
	TCTN3	ENST00000265993.13	TSL:1	c.278C>T	p.Ala93Val	missense	Exon 1 of 14	ENSP00000265993.9	A0A0C4DFN5
	TCTN3	ENST00000614499.5	TSL:1	c.278C>T	p.Ala93Val	missense	Exon 1 of 14	ENSP00000483364.2	A0A804G9W2

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

GnomAD2 exomes AF: 0.00717 AC: 1119 AN: 156070 AF XY: 0.00786

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 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

African (AFR) AF: 0.00206 AC: 65 AN: 31596

American (AMR) AF: 0.00378 AC: 135 AN: 35702

Ashkenazi Jewish (ASJ) AF: 0.00998 AC: 251 AN: 25160

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35738

South Asian (SAS) AF: 0.0151 AC: 1195 AN: 79236

European-Finnish (FIN) AF: 0.00974 AC: 480 AN: 49282

Middle Eastern (MID) AF: 0.0146 AC: 83 AN: 5698

European-Non Finnish (NFE) AF: 0.00593 AC: 6402 AN: 1078972

Other (OTH) AF: 0.00729 AC: 423 AN: 58002

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

African (AFR) AF: 0.00154 AC: 64 AN: 41578

American (AMR) AF: 0.00294 AC: 45 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00691 AC: 24 AN: 3472

East Asian (EAS) AF: 0.000771 AC: 4 AN: 5186

South Asian (SAS) AF: 0.0133 AC: 64 AN: 4826

European-Finnish (FIN) AF: 0.00556 AC: 59 AN: 10614

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00591 AC: 402 AN: 68026

Other (OTH) AF: 0.00569 AC: 12 AN: 2108

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	1	Orofacial-digital syndrome IV;C3553758:Joubert syndrome 18 (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.0059	N
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.0051	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.27
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.089
Sift	Benign	0.14	T
Sift4G	Benign	0.28	T
Polyphen		0.0020	B
Vest4		0.020
MVP		0.85
MPC		0.11
ClinPred		0.0019	T
GERP RS		-0.71
PromoterAI		-0.047	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.028
gMVP		0.28
Mutation Taster		=96/4	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: rs41291570; hg19: chr10-97453433; COSMIC: COSV105061077;