chr3-4979746-C-T

Variant names:

• chr3-4979746-C-T
• rs2053173327
• NM_003670.3:c.28C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003670.3(BHLHE40):​c.28C>T​(p.Pro10Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,423,156 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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: 0.0000014 (0 hom.)
• Consequence: BHLHE40 NM_003670.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.98
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21100205).

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.28C>T	p.Pro10Ser	missense	Exon 1 of 5	NP_003661.1	O14503
	BHLHE40-AS1	NR_037903.3		n.167+49G>A		intron	N/A
	BHLHE40-AS1	NR_125915.1		n.167+49G>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.28C>T	p.Pro10Ser	missense	Exon 1 of 5	ENSP00000256495.3	O14503
	BHLHE40-AS1	ENST00000441386.4	TSL:1	n.620+49G>A		intron	N/A
	BHLHE40	ENST00000931070.1		c.28C>T	p.Pro10Ser	missense	Exon 2 of 6	ENSP00000601129.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1423156 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 704502

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000310 AC: 1 AN: 32298

American (AMR) AF: 0.0000254 AC: 1 AN: 39394

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25462

East Asian (EAS) AF: 0.00 AC: 0 AN: 37000

South Asian (SAS) AF: 0.00 AC: 0 AN: 81700

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50256

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1092478

Other (OTH) AF: 0.00 AC: 0 AN: 58868

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00666416), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	0.16
BayesDel_addAF	Benign	-0.0087	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	1.5	L
PhyloP100		2.0
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.075
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.018	D
Polyphen		0.75	P
Vest4		0.18
MutPred		0.29		Loss of glycosylation at P10 (P = 0.0039)
MVP		0.44
MPC		2.3
ClinPred		0.94	D
GERP RS		4.3
PromoterAI		0.025	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		3.2
Varity_R		0.21
gMVP		0.50
Mutation Taster		=72/28	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: rs2053173327; hg19: chr3-5021431;