11-78658456-G-A

Position:

• chr11-78658456-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP4 BS2

The NM_001098816.3(TENM4):​c.7912C>T​(p.Arg2638Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000478 in 1,613,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00038 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00049 (0 hom.)
• Consequence: TENM4 NM_001098816.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.37

Genes affected

TENM4 (HGNC:29945): (teneurin transmembrane protein 4) The protein encoded by this gene plays a role in establishing proper neuronal connectivity during development. Defects in this gene have been associated with hereditary essential tremor-5. [provided by RefSeq, Oct 2016]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TENM4. . Gene score misZ 2.7323 (greater than the threshold 3.09). Trascript score misZ 3.5261 (greater than threshold 3.09). GenCC has associacion of gene with tremor, hereditary essential, 5.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2646507).
• BS2: High AC in GnomAd4 at 58 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TENM4	NM_001098816.3	c.7912C>T	p.Arg2638Trp	missense_variant	34/34	ENST00000278550.12	NP_001092286.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TENM4	ENST00000278550.12	c.7912C>T	p.Arg2638Trp	missense_variant	34/34	5	NM_001098816.3	ENSP00000278550	P1
TENM4	ENST00000530738.1	c.2801-402C>T		intron_variant		2		ENSP00000431711

Frequencies

GnomAD3 genomes AF: 0.000381 AC: 58 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000691

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000385 AC: 96 AN: 249072 Hom.: 0 AF XY: 0.000392 AC XY: 53 AN XY: 135132

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.000140

Gnomad NFE exome AF: 0.000753

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000488 AC: 713 AN: 1461674 Hom.: 0 Cov.: 31 AF XY: 0.000480 AC XY: 349 AN XY: 727114

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.000300

Gnomad4 NFE exome AF: 0.000596

Gnomad4 OTH exome AF: 0.000282

GnomAD4 genome AF: 0.000381 AC: 58 AN: 152314 Hom.: 0 Cov.: 33 AF XY: 0.000322 AC XY: 24 AN XY: 74478

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000691

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000423 Hom.: 0

Bravo AF: 0.000302

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000356 AC: 3

ExAC AF: 0.000430 AC: 52

EpiCase AF: 0.000218

EpiControl AF: 0.000533

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 16, 2023

Variant summary: TENM4 c.7912C>T (p.Arg2638Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00039 in 249072 control chromosomes. To our knowledge, no occurrence of c.7912C>T in individuals affected with Tremor, Hereditary Essential, 5 and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.26	T
MetaSVM	Uncertain	0.52	D
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	0.83	D
PrimateAI	Benign	0.37	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Uncertain	0.54
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.38
MVP		0.50
MPC		0.63
ClinPred		0.44	T
GERP RS		4.7
Varity_R		0.20
gMVP		0.68

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

Publications

LitVar

Other links and lift over

dbSNP: rs200437630; hg19: chr11-78369501; COSMIC: COSV53682186;