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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, PanelApp Australia
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080477.4. 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
	TENM3	NM_001080477.4	MANE Select	c.4046C>G	p.Ala1349Gly	missense	Exon 22 of 28	NP_001073946.1	Q9P273
	TENM3	NM_001415969.1		c.4067C>G	p.Ala1356Gly	missense	Exon 23 of 29	NP_001402898.1
	TENM3	NM_001415970.1		c.4067C>G	p.Ala1356Gly	missense	Exon 23 of 29	NP_001402899.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TENM3	ENST00000511685.6	TSL:5 MANE Select	c.4046C>G	p.Ala1349Gly	missense	Exon 22 of 28	ENSP00000424226.1	Q9P273
	TENM3	ENST00000851056.1		c.4115C>G	p.Ala1372Gly	missense	Exon 25 of 31	ENSP00000521125.1
	TENM3	ENST00000851057.1		c.4112C>G	p.Ala1371Gly	missense	Exon 25 of 31	ENSP00000521126.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Microphthalmia, isolated, with coloboma 9 (1)
1	-	-	MICROPHTHALMIA, SYNDROMIC 15 (1)

Computational scores

Source: dbNSFP v4.9

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;