12-26122181-T-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_030762.3(BHLHE41):c.1334A>C(p.His445Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000316 in 1,485,456 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000054 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: BHLHE41 NM_030762.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.227

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.017442763).
• BS2: High AC in GnomAd at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BHLHE41	NM_030762.3	c.1334A>C	p.His445Pro	missense_variant	5/5	ENST00000242728.5
SSPN	XM_011520853.4	c.-31+29T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BHLHE41	ENST00000242728.5	c.1334A>C	p.His445Pro	missense_variant	5/5	1	NM_030762.3	P1
SSPN	ENST00000538142.5	c.-31+29T>G		intron_variant		4
SSPN	ENST00000534829.5	n.101+29T>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0000541 AC: 8 AN: 147906 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00204

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000150

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000122 AC: 11 AN: 89814 Hom.: 0 AF XY: 0.000139 AC XY: 7 AN XY: 50508

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00187

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000292 AC: 39 AN: 1337550 Hom.: 0 Cov.: 30 AF XY: 0.0000273 AC XY: 18 AN XY: 658342

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00139

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000380

Gnomad4 OTH exome AF: 0.0000545

GnomAD4 genome AF: 0.0000541 AC: 8 AN: 147906 Hom.: 0 Cov.: 30 AF XY: 0.0000555 AC XY: 4 AN XY: 72048

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00204

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000150

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000288 Hom.: 0

ExAC AF: 0.000196 AC: 6

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

Jan 04, 2022

The c.1334A>C (p.H445P) alteration is located in exon 5 (coding exon 5) of the BHLHE41 gene. This alteration results from a A to C substitution at nucleotide position 1334, causing the histidine (H) at amino acid position 445 to be replaced by a proline (P). 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	0.060
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	19
Dann	Benign	0.64
DEOGEN2	Benign	0.047	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.40	T
M_CAP	Pathogenic	0.48	D
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.17
Sift	Uncertain	0.012	D
Sift4G	Benign	0.30	T
Polyphen		0.0	B
Vest4		0.20
MutPred		0.31		Gain of catalytic residue at P444 (P = 8e-04);
MVP		0.31
ClinPred		0.045	T
GERP RS		0.65
Varity_R		0.15
gMVP		0.36

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: rs764293030; hg19: chr12-26275114;