NM_001080477.4:c.777T>G

Variant names:

• chr4-182628678-T-G
• rs74199039
• NM_001080477.4:c.777T>G

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.777T>G​(p.Gly259Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0778 in 1,596,730 control chromosomes in the GnomAD database, including 5,494 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.064 (417 hom., cov: 31)
  • Exomes 𝑓: 0.079 (5077 hom.)
• Consequence: TENM3 NM_001080477.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.10
• Publications: 16 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=-0.48).
• BP6: Variant 4-182628678-T-G is Benign according to our data. Variant chr4-182628678-T-G is described in ClinVar as Benign. ClinVar VariationId is 257356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.1 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.135 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.777T>G	p.Gly259Gly	synonymous	Exon 5 of 28	NP_001073946.1
	TENM3	NM_001415969.1		c.777T>G	p.Gly259Gly	synonymous	Exon 5 of 29	NP_001402898.1
	TENM3	NM_001415970.1		c.777T>G	p.Gly259Gly	synonymous	Exon 5 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.777T>G	p.Gly259Gly	synonymous	Exon 5 of 28	ENSP00000424226.1
	TENM3	ENST00000851056.1		c.777T>G	p.Gly259Gly	synonymous	Exon 5 of 31	ENSP00000521125.1
	TENM3	ENST00000851057.1		c.777T>G	p.Gly259Gly	synonymous	Exon 5 of 31	ENSP00000521126.1

Frequencies

GnomAD3 genomes AF: 0.0642 AC: 9772 AN: 152102 Hom.: 417 Cov.: 31

Gnomad AFR AF: 0.0254

Gnomad AMI AF: 0.235

Gnomad AMR AF: 0.0597

Gnomad ASJ AF: 0.114

Gnomad EAS AF: 0.143

Gnomad SAS AF: 0.118

Gnomad FIN AF: 0.0285

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0796

Gnomad OTH AF: 0.0659

GnomAD2 exomes AF: 0.0758 AC: 17172 AN: 226490 AF XY: 0.0790

Gnomad AFR exome AF: 0.0222

Gnomad AMR exome AF: 0.0393

Gnomad ASJ exome AF: 0.126

Gnomad EAS exome AF: 0.136

Gnomad FIN exome AF: 0.0366

Gnomad NFE exome AF: 0.0771

Gnomad OTH exome AF: 0.0880

GnomAD4 exome AF: 0.0792 AC: 114439 AN: 1444510 Hom.: 5077 Cov.: 31 AF XY: 0.0805 AC XY: 57673 AN XY: 716812

African (AFR) AF: 0.0235 AC: 778 AN: 33146

American (AMR) AF: 0.0416 AC: 1770 AN: 42534

Ashkenazi Jewish (ASJ) AF: 0.122 AC: 3149 AN: 25732

East Asian (EAS) AF: 0.142 AC: 5546 AN: 39106

South Asian (SAS) AF: 0.113 AC: 9403 AN: 83224

European-Finnish (FIN) AF: 0.0369 AC: 1944 AN: 52618

Middle Eastern (MID) AF: 0.0818 AC: 470 AN: 5746

European-Non Finnish (NFE) AF: 0.0783 AC: 86320 AN: 1102560

Other (OTH) AF: 0.0845 AC: 5059 AN: 59844

GnomAD4 genome AF: 0.0642 AC: 9778 AN: 152220 Hom.: 417 Cov.: 31 AF XY: 0.0629 AC XY: 4682 AN XY: 74422

African (AFR) AF: 0.0254 AC: 1057 AN: 41542

American (AMR) AF: 0.0595 AC: 910 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 396 AN: 3470

East Asian (EAS) AF: 0.143 AC: 740 AN: 5164

South Asian (SAS) AF: 0.119 AC: 572 AN: 4816

European-Finnish (FIN) AF: 0.0285 AC: 303 AN: 10614

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.0796 AC: 5415 AN: 68004

Other (OTH) AF: 0.0666 AC: 141 AN: 2116

Alfa AF: 0.0759 Hom.: 253

Bravo AF: 0.0646

Asia WGS AF: 0.113 AC: 392 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	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	11
DANN	Benign	0.71
PhyloP100		3.1
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: rs74199039; hg19: chr4-183549831; COSMIC: COSV69302447; COSMIC: COSV69302447;