dbSNP rs1064795875: CHD1:p.Arg141Gly (chr5-98902916-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001270.4(CHD1):c.421A>G(p.Arg141Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CHD1
NM_001270.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 2.24

Publications

2 publications found

Variant links:

Genes affected

CHD1 (HGNC:1915): (chromodomain helicase DNA binding protein 1) The CHD family of proteins is characterized by the presence of chromo (chromatin organization modifier) domains and SNF2-related helicase/ATPase domains. CHD genes alter gene expression possibly by modification of chromatin structure thus altering access of the transcriptional apparatus to its chromosomal DNA template. [provided by RefSeq, Jul 2008]

CHD1 Gene-Disease associations (from GenCC):

Pilarowski-Bjornsson syndrome
Inheritance: AD, Unknown Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet
complex neurodevelopmental disorder
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

CHD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.17300662).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHD1	NM_001270.4 link	c.421A>G	p.Arg141Gly	missense_variant	Exon 5 of 36	ENST00000614616.5	NP_001261.2	O14646-1B3KT33

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CHD1	ENST00000614616.5 link	c.421A>G	p.Arg141Gly	missense_variant	Exon 5 of 36	5	NM_001270.4	ENSP00000483667.1	O14646-1
CHD1	ENST00000511067.3 link	c.421A>G	p.Arg141Gly	missense_variant	Exon 5 of 37	5		ENSP00000479403.2	A0A087WVF4
CHD1	ENST00000706140.1 link	n.718A>G		non_coding_transcript_exon_variant	Exon 5 of 34
CHD1	ENST00000706141.1 link	n.421A>G		non_coding_transcript_exon_variant	Exon 5 of 37			ENSP00000516225.1	A0A994J7K7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1451318

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

722506

African (AFR)

AF:

0.00

AC:

AN:

33202

American (AMR)

AF:

0.00

AC:

AN:

44398

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25990

East Asian (EAS)

AF:

0.00

AC:

AN:

39430

South Asian (SAS)

AF:

0.00

AC:

AN:

85616

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52296

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5618

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1104718

Other (OTH)

AF:

0.00

AC:

AN:

60050

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Pilarowski-Bjornsson syndrome

Pathogenic:1

Jun 24, 2019

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Uncertain:1

Oct 06, 2019

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015); This variant is associated with the following publications: (PMID: 28866611) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.088

BayesDel_noAF

Benign

-0.11

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.21

T;T

Eigen

Benign

-0.14

Eigen_PC

Benign

0.036

FATHMM_MKL

Benign

0.39

LIST_S2

Uncertain

0.93

.;D

M_CAP

Benign

0.045

MetaRNN

Benign

0.17

T;T

MetaSVM

Uncertain

-0.070

MutationAssessor

Benign

1.5

L;L

PhyloP100

2.2

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.8

.;N

REVEL

Uncertain

0.31

Sift

Uncertain

0.0040

.;D

Sift4G

Benign

0.15

T;T

Polyphen

0.079

B;B

Vest4

0.26

MutPred

0.38

Loss of stability (P = 0.0086);Loss of stability (P = 0.0086);

MVP

0.73

MPC

0.15

ClinPred

0.82

GERP RS

4.8

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.0

Varity_R

0.21

gMVP

0.28

Mutation Taster

=22/78

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.18

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over