rs71620945

Variant names:

• chr4-182753444-A-C
• rs71620945
• NM_001080477.4:c.3863-6A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001080477.4(TENM3):​c.3863-6A>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.2 in 1,610,272 control chromosomes in the GnomAD database, including 35,121 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2586 hom., cov: 33)
  • Exomes 𝑓: 0.20 (32535 hom.)
• Consequence: TENM3 NM_001080477.4 splice_region, intron
• Scores: Splicing: ADA: 0.00007277
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.599
• Publications: 5 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 4-182753444-A-C is Benign according to our data. Variant chr4-182753444-A-C is described in ClinVar as Benign. ClinVar VariationId is 257352.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.222 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TENM3	NM_001080477.4	MANE Select	c.3863-6A>C		splice_region intron	N/A	NP_001073946.1	Q9P273
	TENM3	NM_001415969.1		c.3884-6A>C		splice_region intron	N/A	NP_001402898.1
	TENM3	NM_001415970.1		c.3884-6A>C		splice_region intron	N/A	NP_001402899.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TENM3	ENST00000511685.6	TSL:5 MANE Select	c.3863-6A>C		splice_region intron	N/A	ENSP00000424226.1	Q9P273
	TENM3	ENST00000851056.1		c.3932-6A>C		splice_region intron	N/A	ENSP00000521125.1
	TENM3	ENST00000851057.1		c.3929-6A>C		splice_region intron	N/A	ENSP00000521126.1

Frequencies

GnomAD3 genomes AF: 0.163 AC: 24791 AN: 152146 Hom.: 2589 Cov.: 33

Gnomad AFR AF: 0.0632

Gnomad AMI AF: 0.186

Gnomad AMR AF: 0.146

Gnomad ASJ AF: 0.117

Gnomad EAS AF: 0.0354

Gnomad SAS AF: 0.117

Gnomad FIN AF: 0.272

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.225

Gnomad OTH AF: 0.164

GnomAD2 exomes AF: 0.171 AC: 42410 AN: 247532 AF XY: 0.175

Gnomad AFR exome AF: 0.0569

Gnomad AMR exome AF: 0.124

Gnomad ASJ exome AF: 0.125

Gnomad EAS exome AF: 0.0349

Gnomad FIN exome AF: 0.260

Gnomad NFE exome AF: 0.223

Gnomad OTH exome AF: 0.179

GnomAD4 exome AF: 0.204 AC: 297203 AN: 1458008 Hom.: 32535 Cov.: 32 AF XY: 0.203 AC XY: 146983 AN XY: 725214

African (AFR) AF: 0.0574 AC: 1917 AN: 33398

American (AMR) AF: 0.126 AC: 5620 AN: 44470

Ashkenazi Jewish (ASJ) AF: 0.121 AC: 3148 AN: 26052

East Asian (EAS) AF: 0.0460 AC: 1826 AN: 39656

South Asian (SAS) AF: 0.123 AC: 10514 AN: 85680

European-Finnish (FIN) AF: 0.259 AC: 13803 AN: 53366

Middle Eastern (MID) AF: 0.176 AC: 1013 AN: 5748

European-Non Finnish (NFE) AF: 0.224 AC: 248247 AN: 1109400

Other (OTH) AF: 0.185 AC: 11115 AN: 60238

GnomAD4 genome AF: 0.163 AC: 24783 AN: 152264 Hom.: 2586 Cov.: 33 AF XY: 0.163 AC XY: 12114 AN XY: 74448

African (AFR) AF: 0.0631 AC: 2623 AN: 41562

American (AMR) AF: 0.145 AC: 2221 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.117 AC: 407 AN: 3472

East Asian (EAS) AF: 0.0355 AC: 184 AN: 5184

South Asian (SAS) AF: 0.117 AC: 562 AN: 4824

European-Finnish (FIN) AF: 0.272 AC: 2877 AN: 10596

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.225 AC: 15325 AN: 68016

Other (OTH) AF: 0.162 AC: 342 AN: 2110

Alfa AF: 0.192 Hom.: 2178

Bravo AF: 0.147

Asia WGS AF: 0.0700 AC: 241 AN: 3478

EpiCase AF: 0.210

EpiControl AF: 0.208

ClinVar

ClinVar submissions

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	-0.87
CADD	Benign	5.1
DANN	Benign	0.57
PhyloP100		0.60
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000073
dbscSNV1_RF	Benign	0.0040
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: rs71620945; hg19: chr4-183674597; COSMIC: COSV69306401;