Variant 3-4982943-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_003670.3(BHLHE40):c.490C>T(p.Arg164Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,774 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: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

BHLHE40
NM_003670.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.31

Variant links:

Genes affected

BHLHE40 (HGNC:1046): (basic helix-loop-helix family member e40) This gene encodes a basic helix-loop-helix protein expressed in various tissues. The encoded protein can interact with ARNTL or compete for E-box binding sites in the promoter of PER1 and repress CLOCK/ARNTL's transactivation of PER1. This gene is believed to be involved in the control of circadian rhythm and cell differentiation. [provided by RefSeq, Feb 2014]

BHLHE40 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.33615643).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BHLHE40	NM_003670.3 link	c.490C>T	p.Arg164Trp	missense_variant	5/5	ENST00000256495.4	NP_003661.1	O14503Q6IB83

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BHLHE40	ENST00000256495.4 link	c.490C>T	p.Arg164Trp	missense_variant	5/5	1	NM_003670.3	ENSP00000256495.3		O14503
BHLHE40	ENST00000467610.1 link	n.1041C>T		non_coding_transcript_exon_variant	4/4	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461774

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727188

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 09, 2024

The c.490C>T (p.R164W) alteration is located in exon 5 (coding exon 5) of the BHLHE40 gene. This alteration results from a C to T substitution at nucleotide position 490, causing the arginine (R) at amino acid position 164 to be replaced by a tryptophan (W). 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

0.17

BayesDel_addAF

Benign

-0.059

BayesDel_noAF

Benign

-0.32

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.44

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Benign

0.60

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.048

MetaRNN

Benign

0.34

MetaSVM

Benign

-0.69

MutationAssessor

Uncertain

2.0

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-3.6

REVEL

Benign

0.26

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0070

Polyphen

1.0

Vest4

0.28

MutPred

0.52

Loss of disorder (P = 0.0272);

MVP

0.14

MPC

0.70

ClinPred

0.99

GERP RS

5.0

Varity_R

0.40

gMVP

0.24

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over