chr3-4979761-C-T

Variant names:

• chr3-4979761-C-T
• rs1248007271
• NM_003670.3:c.43C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003670.3(BHLHE40):​c.43C>T​(p.Pro15Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000697 in 1,433,944 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: BHLHE40 NM_003670.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0690
• Publications: 0 publications found

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-AS1 (HGNC:44471): (BHLHE40 antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.059838235).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003670.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BHLHE40	NM_003670.3	MANE Select	c.43C>T	p.Pro15Ser	missense	Exon 1 of 5	NP_003661.1	O14503
	BHLHE40-AS1	NR_037903.3		n.167+34G>A		intron	N/A
	BHLHE40-AS1	NR_125915.1		n.167+34G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BHLHE40	ENST00000256495.4	TSL:1 MANE Select	c.43C>T	p.Pro15Ser	missense	Exon 1 of 5	ENSP00000256495.3	O14503
	BHLHE40-AS1	ENST00000441386.4	TSL:1	n.620+34G>A		intron	N/A
	BHLHE40	ENST00000931070.1		c.43C>T	p.Pro15Ser	missense	Exon 2 of 6	ENSP00000601129.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.97e-7 AC: 1 AN: 1433944 Hom.: 0 Cov.: 32 AF XY: 0.00000141 AC XY: 1 AN XY: 710940

African (AFR) AF: 0.0000307 AC: 1 AN: 32594

American (AMR) AF: 0.00 AC: 0 AN: 40936

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25616

East Asian (EAS) AF: 0.00 AC: 0 AN: 37704

South Asian (SAS) AF: 0.00 AC: 0 AN: 82694

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51104

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1098260

Other (OTH) AF: 0.00 AC: 0 AN: 59290

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	20
DANN	Benign	0.94
DEOGEN2	Benign	0.081	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.060	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.069
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.052
Sift	Benign	0.41	T
Sift4G	Benign	0.72	T
Polyphen		0.0070	B
Vest4		0.090
MutPred		0.17		Loss of glycosylation at P10 (P = 0.0039)
MVP		0.23
MPC		1.2
ClinPred		0.14	T
GERP RS		2.0
PromoterAI		-0.031	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.046
gMVP		0.38
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs1248007271; hg19: chr3-5021446;