4-182680694-T-C

Variant names:

• chr4-182680694-T-C
• rs2871328
• NM_001080477.4:c.1791T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001080477.4(TENM3):​c.1791T>C​(p.Ser597Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.397 in 1,592,062 control chromosomes in the GnomAD database, including 131,795 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (14515 hom., cov: 31)
  • Exomes 𝑓: 0.39 (117280 hom.)
• Consequence: TENM3 NM_001080477.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.392
• Publications: 17 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• 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=-0.52).
• BP6: Variant 4-182680694-T-C is Benign according to our data. Variant chr4-182680694-T-C is described in ClinVar as Benign. ClinVar VariationId is 257347.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.392 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.757 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TENM3	NM_001080477.4	MANE Select	c.1791T>C	p.Ser597Ser	synonymous	Exon 10 of 28	NP_001073946.1
	TENM3	NM_001415969.1		c.1791T>C	p.Ser597Ser	synonymous	Exon 10 of 29	NP_001402898.1
	TENM3	NM_001415970.1		c.1791T>C	p.Ser597Ser	synonymous	Exon 10 of 29	NP_001402899.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TENM3	ENST00000511685.6	TSL:5 MANE Select	c.1791T>C	p.Ser597Ser	synonymous	Exon 10 of 28	ENSP00000424226.1
	TENM3	ENST00000502950.1	TSL:2	n.178T>C		non_coding_transcript_exon	Exon 2 of 15
	TENM3	ENST00000507737.1	TSL:3	n.323T>C		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.425 AC: 64604 AN: 151840 Hom.: 14484 Cov.: 31

Gnomad AFR AF: 0.434

Gnomad AMI AF: 0.487

Gnomad AMR AF: 0.515

Gnomad ASJ AF: 0.429

Gnomad EAS AF: 0.777

Gnomad SAS AF: 0.511

Gnomad FIN AF: 0.424

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.368

Gnomad OTH AF: 0.393

GnomAD2 exomes AF: 0.453 AC: 105879 AN: 233488 AF XY: 0.446

Gnomad AFR exome AF: 0.425

Gnomad AMR exome AF: 0.618

Gnomad ASJ exome AF: 0.425

Gnomad EAS exome AF: 0.792

Gnomad FIN exome AF: 0.419

Gnomad NFE exome AF: 0.358

Gnomad OTH exome AF: 0.422

GnomAD4 exome AF: 0.394 AC: 567317 AN: 1440104 Hom.: 117280 Cov.: 36 AF XY: 0.397 AC XY: 283854 AN XY: 714826

African (AFR) AF: 0.428 AC: 13818 AN: 32304

American (AMR) AF: 0.602 AC: 23433 AN: 38956

Ashkenazi Jewish (ASJ) AF: 0.419 AC: 10580 AN: 25266

East Asian (EAS) AF: 0.768 AC: 30265 AN: 39404

South Asian (SAS) AF: 0.499 AC: 41683 AN: 83460

European-Finnish (FIN) AF: 0.420 AC: 22334 AN: 53228

Middle Eastern (MID) AF: 0.322 AC: 1838 AN: 5702

European-Non Finnish (NFE) AF: 0.362 AC: 399100 AN: 1102350

Other (OTH) AF: 0.408 AC: 24266 AN: 59434

GnomAD4 genome AF: 0.426 AC: 64682 AN: 151958 Hom.: 14515 Cov.: 31 AF XY: 0.433 AC XY: 32128 AN XY: 74262

African (AFR) AF: 0.434 AC: 17980 AN: 41414

American (AMR) AF: 0.516 AC: 7885 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.429 AC: 1487 AN: 3466

East Asian (EAS) AF: 0.777 AC: 3998 AN: 5148

South Asian (SAS) AF: 0.513 AC: 2460 AN: 4798

European-Finnish (FIN) AF: 0.424 AC: 4477 AN: 10562

Middle Eastern (MID) AF: 0.293 AC: 86 AN: 294

European-Non Finnish (NFE) AF: 0.368 AC: 25031 AN: 67974

Other (OTH) AF: 0.395 AC: 834 AN: 2112

Alfa AF: 0.386 Hom.: 10672

Bravo AF: 0.432

Asia WGS AF: 0.638 AC: 2220 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Microphthalmia, isolated, with coloboma 9 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	6.9
DANN	Benign	0.74
PhyloP100		0.39
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs2871328; hg19: chr4-183601847; COSMIC: COSV108246382;