4-182754413-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, TENM3
• 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 id is 487483.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TENM3	NM_001080477.4	c.4046C>G	p.Ala1349Gly	missense_variant	22/28	ENST00000511685.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TENM3	ENST00000511685.6	c.4046C>G	p.Ala1349Gly	missense_variant	22/28	5	NM_001080477.4	P1
TENM3	ENST00000502950.1	n.2454C>G		non_coding_transcript_exon_variant	15/15	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

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 30, 2019

- -

Microphthalmia, isolated, with coloboma 9 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

-

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
MutationTaster	Benign	1.0	D;D
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1243762658; hg19: chr4-183675566;