chr11-78658440-T-C

Position:

• chr11-78658440-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001098816.3(TENM4):​c.7928A>G​(p.Asn2643Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TENM4 NM_001098816.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.63

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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=0.11904907).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TENM4	NM_001098816.3	c.7928A>G	p.Asn2643Ser	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.7928A>G	p.Asn2643Ser	missense_variant	34/34	5	NM_001098816.3	ENSP00000278550	P1
TENM4	ENST00000530738.1	c.2801-386A>G		intron_variant		2		ENSP00000431711

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

Ambry Genetics

May 25, 2022

The c.7928A>G (p.N2643S) alteration is located in exon 34 (coding exon 30) of the TENM4 gene. This alteration results from a A to G substitution at nucleotide position 7928, causing the asparagine (N) at amino acid position 2643 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.025
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.12	T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	0.84	D
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.19
Sift	Benign	0.45	T
Sift4G	Benign	0.51	T
Polyphen		0.28	B
Vest4		0.058
MutPred		0.23		Gain of disorder (P = 0.058);
MVP		0.44
MPC		0.35
ClinPred		0.72	D
GERP RS		4.5
Varity_R		0.12
gMVP		0.37

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-78369485;