4-182346733-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001080477.4(TENM3):c.315C>T(p.Leu105=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00722 in 1,613,516 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0067 (5 hom., cov: 31)
  • Exomes 𝑓: 0.0073 (51 hom.)
• Consequence: TENM3 NM_001080477.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.802

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 4-182346733-C-T is Benign according to our data. Variant chr4-182346733-C-T is described in ClinVar as [Benign]. Clinvar id is 774445.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-182346733-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.802 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00667 (1015/152102) while in subpopulation NFE AF= 0.00999 (679/67994). AF 95% confidence interval is 0.00936. There are 5 homozygotes in gnomad4. There are 491 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TENM3	NM_001080477.4	c.315C>T	p.Leu105=	synonymous_variant	3/28	ENST00000511685.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TENM3	ENST00000511685.6	c.315C>T	p.Leu105=	synonymous_variant	3/28	5	NM_001080477.4	P1
TENM3	ENST00000513201.1	n.565C>T		non_coding_transcript_exon_variant	3/4	1
TENM3	ENST00000512480.5	c.315C>T	p.Leu105=	synonymous_variant	3/3	3

Frequencies

GnomAD3 genomes AF: 0.00668 AC: 1015 AN: 151984 Hom.: 5 Cov.: 31

Gnomad AFR AF: 0.00169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00655

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.0126

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00999

Gnomad OTH AF: 0.00766

GnomAD3 exomes AF: 0.00654 AC: 1627 AN: 248624 Hom.: 12 AF XY: 0.00659 AC XY: 888 AN XY: 134808

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.00468

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00262

Gnomad FIN exome AF: 0.0124

Gnomad NFE exome AF: 0.00931

Gnomad OTH exome AF: 0.00546

GnomAD4 exome AF: 0.00727 AC: 10629 AN: 1461414 Hom.: 51 Cov.: 33 AF XY: 0.00712 AC XY: 5173 AN XY: 726944

Gnomad4 AFR exome AF: 0.00122

Gnomad4 AMR exome AF: 0.00517

Gnomad4 ASJ exome AF: 0.00153

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00347

Gnomad4 FIN exome AF: 0.0126

Gnomad4 NFE exome AF: 0.00805

Gnomad4 OTH exome AF: 0.00616

GnomAD4 genome AF: 0.00667 AC: 1015 AN: 152102 Hom.: 5 Cov.: 31 AF XY: 0.00660 AC XY: 491 AN XY: 74344

Gnomad4 AFR AF: 0.00169

Gnomad4 AMR AF: 0.00654

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.0126

Gnomad4 NFE AF: 0.00999

Gnomad4 OTH AF: 0.00758

Alfa AF: 0.00811 Hom.: 1

Bravo AF: 0.00574

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00889

EpiControl AF: 0.00946

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2022	TENM3: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 23, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 10, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
Cadd	Benign	4.0
Dann	Benign	0.74

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: rs144353515; hg19: chr4-183267886;