4-182346733-C-T

Variant names:

• chr4-182346733-C-T
• rs144353515
• NM_001080477.4:c.315C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001080477.4(TENM3):​c.315C>T​(p.Leu105Leu) 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:4
• Conservation: PhyloP100: -0.802
• Publications: 1 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: Benign. The variant received -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 VariationId is 774445.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR,AD gene

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.315C>T	p.Leu105Leu	synonymous	Exon 3 of 28	NP_001073946.1	Q9P273
	TENM3	NM_001415969.1		c.315C>T	p.Leu105Leu	synonymous	Exon 3 of 29	NP_001402898.1
	TENM3	NM_001415970.1		c.315C>T	p.Leu105Leu	synonymous	Exon 3 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.315C>T	p.Leu105Leu	synonymous	Exon 3 of 28	ENSP00000424226.1	Q9P273
	TENM3	ENST00000513201.1	TSL:1	n.565C>T		non_coding_transcript_exon	Exon 3 of 4
	TENM3	ENST00000851056.1		c.315C>T	p.Leu105Leu	synonymous	Exon 3 of 31	ENSP00000521125.1

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

GnomAD2 exomes AF: 0.00654 AC: 1627 AN: 248624 AF XY: 0.00659

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 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

African (AFR) AF: 0.00122 AC: 41 AN: 33478

American (AMR) AF: 0.00517 AC: 231 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00153 AC: 40 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00347 AC: 299 AN: 86182

European-Finnish (FIN) AF: 0.0126 AC: 671 AN: 53394

Middle Eastern (MID) AF: 0.00485 AC: 28 AN: 5768

European-Non Finnish (NFE) AF: 0.00805 AC: 8947 AN: 1111716

Other (OTH) AF: 0.00616 AC: 372 AN: 60370

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

African (AFR) AF: 0.00169 AC: 70 AN: 41494

American (AMR) AF: 0.00654 AC: 100 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4816

European-Finnish (FIN) AF: 0.0126 AC: 133 AN: 10578

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00999 AC: 679 AN: 67994

Other (OTH) AF: 0.00758 AC: 16 AN: 2112

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	4.0
DANN	Benign	0.74
PhyloP100		-0.80
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs144353515; hg19: chr4-183267886;