4-182346789-C-G

Position:

• chr4-182346789-C-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP2 BP4_Strong

The NM_001080477.4(TENM3):​c.371C>G​(p.Ala124Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: TENM3 NM_001080477.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.15

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TENM3. . Gene score misZ 3.2996 (greater than the threshold 3.09). Trascript score misZ 3.8249 (greater than threshold 3.09). GenCC has associacion of gene with microphthalmia, isolated, with coloboma, microphthalmia, isolated, with coloboma 9.
• BP4: Computational evidence support a benign effect (MetaRNN=0.054154247).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TENM3	NM_001080477.4	c.371C>G	p.Ala124Gly	missense_variant	3/28	ENST00000511685.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TENM3	ENST00000511685.6	c.371C>G	p.Ala124Gly	missense_variant	3/28	5	NM_001080477.4	P1
TENM3	ENST00000513201.1	n.621C>G		non_coding_transcript_exon_variant	3/4	1
TENM3	ENST00000512480.5	c.371C>G	p.Ala124Gly	missense_variant	3/3	3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 30, 2024

The c.371C>G (p.A124G) alteration is located in exon 2 (coding exon 2) of the TENM3 gene. This alteration results from a C to G substitution at nucleotide position 371, causing the alanine (A) at amino acid position 124 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	23
DANN	Benign	0.25
DEOGEN2	Benign	0.044	.;T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.63	D
LIST_S2	Uncertain	0.86	D;T
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.054	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.69	.;N
MutationTaster	Benign	0.81	N;N
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	1.1	N;N
REVEL	Benign	0.082
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0010	B;B
Vest4		0.13
MutPred		0.32		Loss of stability (P = 0.0189);Loss of stability (P = 0.0189);
MVP		0.043
MPC		0.27
ClinPred		0.30	T
GERP RS		4.0
Varity_R		0.069
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-183267942;