rs10866256

Positions:

• chr4-182731022-C-A
• chr4-182731022-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001080477.4(TENM3):​c.2850C>A​(p.Asp950Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 7/10 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D950V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TENM3 NM_001080477.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.66

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 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=0.090435386).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TENM3	NM_001080477.4	c.2850C>A	p.Asp950Glu	missense_variant	16/28	ENST00000511685.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TENM3	ENST00000511685.6	c.2850C>A	p.Asp950Glu	missense_variant	16/28	5	NM_001080477.4	P1
TENM3	ENST00000502950.1	n.1237C>A		non_coding_transcript_exon_variant	8/15	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_noAF	Pathogenic	0.18
CADD	Benign	17
DEOGEN2	Benign	0.064	T
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.090	T
PROVEAN	Benign	-0.64	N
Sift	Benign	0.65	T
Sift4G	Benign	0.31	T
Vest4		0.14
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs10866256; hg19: chr4-183652175;