dbSNP rs557608885: BARHL1:p.Ser167Cys (chr9-132587362-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_020064.4(BARHL1):c.500C>G(p.Ser167Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,202 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S167F) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

BARHL1
NM_020064.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.79

Publications

0 publications found

Variant links:

Genes affected

BARHL1 (HGNC:953): (BarH like homeobox 1) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to act upstream of or within several processes, including negative regulation of neuron apoptotic process; nervous system development; and sensory perception of sound. Predicted to be part of chromatin. Predicted to be active in nucleus. Biomarker of Alzheimer's disease; high grade glioma; and triple-receptor negative breast cancer. [provided by Alliance of Genome Resources, Apr 2022]

BARHL1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BARHL1	NM_020064.4 link	c.500C>G	p.Ser167Cys	missense_variant	Exon 2 of 3	ENST00000263610.7	NP_064448.1	Q9BZE3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BARHL1	ENST00000263610.7 link	c.500C>G	p.Ser167Cys	missense_variant	Exon 2 of 3	1	NM_020064.4	ENSP00000263610.2		Q9BZE3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1458202

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

725154

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

33440

American (AMR)

AF:

0.00

AC:

AN:

44518

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26016

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39620

South Asian (SAS)

AF:

0.00

AC:

AN:

85418

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52188

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5474

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111270

Other (OTH)

AF:

0.0000166

AC:

AN:

60258

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.58

BayesDel_addAF

Uncertain

0.098

BayesDel_noAF

Benign

-0.10

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.55

D;D

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.88

.;D

M_CAP

Uncertain

0.23

MetaRNN

Uncertain

0.62

D;D

MetaSVM

Uncertain

0.74

MutationAssessor

Benign

1.9

L;L

PhyloP100

2.8

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-2.9

D;D

REVEL

Uncertain

0.46

Sift

Benign

0.039

D;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

0.99

D;D

Vest4

0.52

MutPred

0.23

Loss of phosphorylation at S167 (P = 0.0023);Loss of phosphorylation at S167 (P = 0.0023);

MVP

0.96

MPC

1.8

ClinPred

0.97

GERP RS

4.9

Varity_R

0.26

gMVP

0.59

Mutation Taster

=50/50

(source)

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

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rs557608885

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over