12-26122509-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_030762.3(BHLHE41):c.1006C>T(p.Pro336Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000169 in 1,302,852 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00018 (1 hom.)
• Consequence: BHLHE41 NM_030762.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.48

Genes affected

BHLHE41 (HGNC:16617): (basic helix-loop-helix family member e41) 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. Defects in this gene are associated with the short sleep phenotype. [provided by RefSeq, Feb 2014]

SSPN (HGNC:11322): (sarcospan) This gene encodes a member of the dystrophin-glycoprotein complex (DGC). The DGC spans the sarcolemma and is comprised of dystrophin, syntrophin, alpha- and beta-dystroglycans and sarcoglycans. The DGC provides a structural link between the subsarcolemmal cytoskeleton and the extracellular matrix of muscle cells. Two alternatively spliced transcript variants that encode different protein isoforms have been described. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3221102).
• BS2: High AC in GnomAd at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BHLHE41	NM_030762.3	c.1006C>T	p.Pro336Ser	missense_variant	5/5	ENST00000242728.5
SSPN	XM_011520853.4	c.-31+357G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BHLHE41	ENST00000242728.5	c.1006C>T	p.Pro336Ser	missense_variant	5/5	1	NM_030762.3	P1
SSPN	ENST00000538142.5	c.-31+357G>A		intron_variant		4
SSPN	ENST00000534829.5	n.101+357G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.000116 AC: 17 AN: 147052 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000246

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000672

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000111

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000211

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000757 AC: 4 AN: 52866 Hom.: 0 AF XY: 0.0000990 AC XY: 3 AN XY: 30294

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000892

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000110

Gnomad OTH exome AF: 0.000634

GnomAD4 exome AF: 0.000176 AC: 203 AN: 1155800 Hom.: 1 Cov.: 30 AF XY: 0.000170 AC XY: 96 AN XY: 564690

Gnomad4 AFR exome AF: 0.0000850

Gnomad4 AMR exome AF: 0.0000512

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000381

Gnomad4 NFE exome AF: 0.000198

Gnomad4 OTH exome AF: 0.000246

GnomAD4 genome AF: 0.000116 AC: 17 AN: 147052 Hom.: 0 Cov.: 30 AF XY: 0.000154 AC XY: 11 AN XY: 71616

Gnomad4 AFR AF: 0.0000246

Gnomad4 AMR AF: 0.0000672

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000111

Gnomad4 NFE AF: 0.000211

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000102

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

Oct 30, 2023

The c.1006C>T (p.P336S) alteration is located in exon 5 (coding exon 5) of the BHLHE41 gene. This alteration results from a C to T substitution at nucleotide position 1006, causing the proline (P) at amino acid position 336 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	0.089
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	21
Dann	Benign	0.97
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.56	T
M_CAP	Pathogenic	0.89	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	0.81	L
MutationTaster	Benign	0.62	N
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.21
Sift	Benign	0.41	T
Sift4G	Benign	0.42	T
Polyphen		0.98	D
Vest4		0.18
MutPred		0.36		Gain of catalytic residue at G334 (P = 0);
MVP		0.22
ClinPred		0.10	T
GERP RS		2.1
Varity_R		0.062
gMVP		0.40

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

Other links and lift over

dbSNP: rs959336645; hg19: chr12-26275442;