4-182754413-C-G

Variant names:

• chr4-182754413-C-G
• rs1243762658
• NM_001080477.4:c.4046C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_001080477.4(TENM3):​c.4046C>G​(p.Ala1349Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TENM3 NM_001080477.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.91
• Publications: 3 publications found

Genes affected

TENM3 (HGNC:29944): (teneurin transmembrane protein 3) This gene encodes a member of the teneurin transmembrane protein family. The encoded protein may be involved in the regulation of neuronal development including development of the visual pathway. Mutations in this gene have been associated with microphthalmia and developmental dysplasia of the hip. [provided by RefSeq, Jan 2023]

TENM3 Gene-Disease associations (from GenCC):

• microphthalmia, isolated, with coloboma 9

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• microphthalmia, isolated, with coloboma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-182754413-C-G is Pathogenic according to our data. Variant chr4-182754413-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 487483.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TENM3	NM_001080477.4	c.4046C>G	p.Ala1349Gly	missense_variant	Exon 22 of 28	ENST00000511685.6	NP_001073946.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TENM3	ENST00000511685.6	c.4046C>G	p.Ala1349Gly	missense_variant	Exon 22 of 28	5	NM_001080477.4	ENSP00000424226.1
TENM3	ENST00000502950.1	n.2454C>G		non_coding_transcript_exon_variant	Exon 15 of 15	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

MICROPHTHALMIA, SYNDROMIC 15 Pathogenic:1

Jul 30, 2019

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Microphthalmia, isolated, with coloboma 9 Pathogenic:1

-

Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant [c.4046C>G (p.Ala1349Gly)] is found to be compound heterozygous with another variant [c.7687C>T (p.Arg2563Trp)] in TENM3 gene. These variations are not reported in the 1000 Genomes database and are predicted to be damaging by SIFT and PolyPhen. The region is conserved across species. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.25	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		7.9
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.65
Sift	Benign	0.039	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.88	P
Vest4		0.61
MutPred		0.67		Gain of catalytic residue at P1345 (P = 0.0696);
MVP		0.17
MPC		0.27
ClinPred		0.97	D
GERP RS		5.6
Varity_R		0.32
gMVP		0.76
Mutation Taster		=6/94	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1243762658; hg19: chr4-183675566;