Genetic Variant BHLHE22:p.Arg3Ser (chr8-64580797-C-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_152414.5(BHLHE22):c.7C>A(p.Arg3Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000173 in 1,384,422 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 0.000034 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

BHLHE22
NM_152414.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.47

Variant links:

Genes affected

BHLHE22 (HGNC:11963): (basic helix-loop-helix family member e22) This gene encodes a protein that belongs to the basic helix-loop-helix (bHLH) family of transcription factors that regulate cell fate determination, proliferation, and differentiation. A similar protein in mouse is required for the development of the dorsal cochlear nuclei, and is thought to play a role in in the differentiation of neurons involved in sensory input. The mouse protein also functions in retinogenesis. [provided by RefSeq, Oct 2016]

BHLHE22 links:

BHLHE22-AS1 (HGNC:56147): (BHLHE22 antisense RNA 1)

BHLHE22-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.05318719).

BS2

High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BHLHE22	NM_152414.5 link	c.7C>A	p.Arg3Ser	missense_variant	Exon 1 of 1	ENST00000321870.3	NP_689627.1	Q8NFJ8B4DF88
BHLHE22-AS1	NR_152770.1 link	n.175+921G>T		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
BHLHE22	ENST00000321870.3 link	c.7C>A	p.Arg3Ser	missense_variant	Exon 1 of 1	6	NM_152414.5	ENSP00000318799.1	Q8NFJ8
BHLHE22-AS1	ENST00000517909.1 link	n.171+921G>T		intron_variant	Intron 1 of 1	2
BHLHE22-AS1	ENST00000665275.1 link	n.94+921G>T		intron_variant	Intron 1 of 1
BHLHE22-AS1	ENST00000670034.1 link	n.204+921G>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.0000341

AC:

AN:

146678

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00147

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000532

AC:

AN:

56426

Hom.:

AF XY:

0.0000612

AC XY:

AN XY:

32698

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000598

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:

0.0000154

AC:

AN:

1237744

Hom.:

Cov.:

AF XY:

0.0000181

AC XY:

AN XY:

607594

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000738

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000299

Gnomad4 OTH exome

AF:

0.0000200

GnomAD4 genome

AF:

0.0000341

AC:

AN:

146678

Hom.:

Cov.:

AF XY:

0.0000419

AC XY:

AN XY:

71552

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00147

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000120

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 08, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.7C>A (p.R3S) alteration is located in exon 1 (coding exon 1) of the BHLHE22 gene. This alteration results from a C to A substitution at nucleotide position 7, causing the arginine (R) at amino acid position 3 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

Uncertain

0.48

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

Eigen

Benign

0.041

Eigen_PC

Benign

0.091

FATHMM_MKL

Benign

0.30

LIST_S2

Benign

0.51

M_CAP

Pathogenic

1.0

MetaRNN

Benign

0.053

MetaSVM

Pathogenic

0.79

MutationAssessor

Benign

1.5

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

-1.2

REVEL

Pathogenic

0.65

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.68

Vest4

0.20

MutPred

0.27

Gain of glycosylation at R3 (P = 0.0112);

MVP

0.59

MPC

1.8

ClinPred

0.39

GERP RS

3.5

Varity_R

0.67

gMVP

0.47

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over