NM_030762.3:c.1171G>A

Variant names:

• chr12-26122344-C-T
• rs765117312
• NM_030762.3:c.1171G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_030762.3(BHLHE41):​c.1171G>A​(p.Gly391Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000017 in 1,174,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: BHLHE41 NM_030762.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.40
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19726852).
• BS2: High AC in GnomAdExome4 at 16 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030762.3. 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
	BHLHE41	NM_030762.3	MANE Select	c.1171G>A	p.Gly391Ser	missense	Exon 5 of 5	NP_110389.1	Q9C0J9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BHLHE41	ENST00000242728.5	TSL:1 MANE Select	c.1171G>A	p.Gly391Ser	missense	Exon 5 of 5	ENSP00000242728.4	Q9C0J9
	BHLHE41	ENST00000957109.1		c.1177G>A	p.Gly393Ser	missense	Exon 5 of 5	ENSP00000627168.1
	SSPN	ENST00000538142.5	TSL:4	c.-31+192C>T		intron	N/A	ENSP00000445360.1	F5H381

Frequencies

GnomAD3 genomes AF: 0.0000273 AC: 4 AN: 146702 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000606

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000554 AC: 1 AN: 1806 AF XY: 0.000923

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00102

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000156 AC: 16 AN: 1027368 Hom.: 0 Cov.: 30 AF XY: 0.0000144 AC XY: 7 AN XY: 486174

African (AFR) AF: 0.00 AC: 0 AN: 20698

American (AMR) AF: 0.00 AC: 0 AN: 6574

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11460

East Asian (EAS) AF: 0.00 AC: 0 AN: 21168

South Asian (SAS) AF: 0.00 AC: 0 AN: 19340

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20056

Middle Eastern (MID) AF: 0.000759 AC: 2 AN: 2636

European-Non Finnish (NFE) AF: 0.0000147 AC: 13 AN: 886182

Other (OTH) AF: 0.0000255 AC: 1 AN: 39254

GnomAD4 genome AF: 0.0000273 AC: 4 AN: 146702 Hom.: 0 Cov.: 30 AF XY: 0.0000140 AC XY: 1 AN XY: 71408

African (AFR) AF: 0.00 AC: 0 AN: 40464

American (AMR) AF: 0.00 AC: 0 AN: 14862

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3400

East Asian (EAS) AF: 0.00 AC: 0 AN: 4832

South Asian (SAS) AF: 0.00 AC: 0 AN: 4622

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9288

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.0000606 AC: 4 AN: 65984

Other (OTH) AF: 0.00 AC: 0 AN: 2040

Alfa AF: 0.000108 Hom.: 0

ExAC AF: 0.0000131 AC: 1

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	0.29
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.067
Eigen_PC	Benign	-0.10
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.73	T
M_CAP	Pathogenic	0.92	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.4
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.32
Sift	Benign	0.31	T
Sift4G	Benign	0.074	T
Polyphen		0.79	P
Vest4		0.075
MutPred		0.34		Gain of glycosylation at G391 (P = 0)
MVP		0.51
ClinPred		0.12	T
GERP RS		2.1
PromoterAI		-0.047	Neutral
Varity_R		0.15
gMVP		0.63
Mutation Taster		=87/13	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: rs765117312; hg19: chr12-26275277;