3-4983390-G-A

Position:

• chr3-4983390-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003670.3(BHLHE40):​c.937G>A​(p.Gly313Ser) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BHLHE40 NM_003670.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.49

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15423718).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BHLHE40	NM_003670.3	c.937G>A	p.Gly313Ser	missense_variant	5/5	ENST00000256495.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BHLHE40	ENST00000256495.4	c.937G>A	p.Gly313Ser	missense_variant	5/5	1	NM_003670.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

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

Nov 18, 2022

The c.937G>A (p.G313S) alteration is located in exon 5 (coding exon 5) of the BHLHE40 gene. This alteration results from a G to A substitution at nucleotide position 937, causing the glycine (G) at amino acid position 313 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	0.074
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	19
DANN	Benign	0.92
DEOGEN2	Benign	0.086	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	0.075	N
MutationTaster	Benign	0.85	D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.25
Sift	Benign	0.22	T
Sift4G	Benign	0.57	T
Polyphen		0.094	B
Vest4		0.14
MutPred		0.25		Gain of sheet (P = 0.0266);
MVP		0.58
MPC		0.20
ClinPred		0.35	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.042
gMVP		0.30

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: chr3-5025075;