11-78658455-C-T

Position:

• chr11-78658455-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2 BP4_Strong BP6_Moderate BS1 BS2

The NM_001098816.3(TENM4):​c.7913G>A​(p.Arg2638Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00154 in 1,614,020 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2638W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0080 (20 hom., cov: 33)
  • Exomes 𝑓: 0.00087 (19 hom.)
• Consequence: TENM4 NM_001098816.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.77

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 Benign. Variant got -13 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=0.0059633255).
• BP6: Variant 11-78658455-C-T is Benign according to our data. Variant chr11-78658455-C-T is described in ClinVar as [Benign]. Clinvar id is 787384.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00797 (1214/152326) while in subpopulation AFR AF= 0.0276 (1146/41570). AF 95% confidence interval is 0.0262. There are 20 homozygotes in gnomad4. There are 564 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1214 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TENM4	NM_001098816.3	c.7913G>A	p.Arg2638Gln	missense_variant	34/34	ENST00000278550.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TENM4	ENST00000278550.12	c.7913G>A	p.Arg2638Gln	missense_variant	34/34	5	NM_001098816.3	P1
TENM4	ENST00000530738.1	c.2801-401G>A		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.00797 AC: 1213 AN: 152208 Hom.: 20 Cov.: 33

Gnomad AFR AF: 0.0276

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00716

GnomAD3 exomes AF: 0.00194 AC: 483 AN: 249148 Hom.: 6 AF XY: 0.00146 AC XY: 198 AN XY: 135166

Gnomad AFR exome AF: 0.0270

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000784

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000874 AC: 1277 AN: 1461694 Hom.: 19 Cov.: 31 AF XY: 0.000777 AC XY: 565 AN XY: 727126

Gnomad4 AFR exome AF: 0.0284

Gnomad4 AMR exome AF: 0.00148

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000858

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000558

Gnomad4 OTH exome AF: 0.00189

GnomAD4 genome AF: 0.00797 AC: 1214 AN: 152326 Hom.: 20 Cov.: 33 AF XY: 0.00757 AC XY: 564 AN XY: 74492

Gnomad4 AFR AF: 0.0276

Gnomad4 AMR AF: 0.00261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00709

Alfa AF: 0.00136 Hom.: 4

Bravo AF: 0.00895

ESP6500AA AF: 0.0272 AC: 113

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00245 AC: 297

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.36
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0060	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.3	L
MutationTaster	Benign	0.67	N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.21
Sift	Benign	0.15	T
Sift4G	Benign	0.26	T
Polyphen		0.056	B
Vest4		0.070
MVP		0.17
MPC		0.32
ClinPred		0.013	T
GERP RS		1.8
Varity_R		0.080
gMVP		0.53

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: rs114100394; hg19: chr11-78369500;