Genetic Variant NM_001270.4:c.4976G>C (chr5-98856537-C-G) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001270.4(CHD1):c.4976G>C(p.Arg1659Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000157 in 1,461,656 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

CHD1
NM_001270.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.16

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAdExome4 at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHD1	NM_001270.4 link	c.4976G>C	p.Arg1659Thr	missense_variant	Exon 36 of 36	ENST00000614616.5	NP_001261.2	O14646-1B3KT33

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHD1	ENST00000614616.5 link	c.4976G>C	p.Arg1659Thr	missense_variant	Exon 36 of 36	5	NM_001270.4	ENSP00000483667.1		O14646-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000157

AC:

AN:

1461656

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727108

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000189

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pilarowski-Bjornsson syndrome

Uncertain:2

Jun 04, 2021

New York Genome Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The inherited heterozygous c.4976G>C (p.Arg1659Thr) missense variant identified in the CHD1 gene has not been reported in affected individuals in the literature. The variant is absent from gnomAD(v3) database suggesting it is not a common benign variant in the populations represented in that database. The variant affects an evolutionarily conserved residue and is predicted deleterious by multiple in silico prediction tools (CADD score = 25, REVEL score =0.681). Based on the available evidence, the inherited heterozygous c.4976G>C (p.Arg1659Thr) missense variant identified in the CHD1 gene is reported as a variant of uncertain significance. -

Aug 25, 2023

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CHD1 c.4976G>C (p.Arg1659Thr) variant, to our knowledge, has not been reported in the medical literature. The variant is absent from the general population (gnomAD v.2.1.1), indicating it is not a common variant. Note that five of the six patients described with Pilarowski-Bjornsson syndrome had pathogenic variants affecting an arginine (Pilarowski et al., PMID: 28866611). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to CHD1 function. This variant has been reported in the ClinVar database as a variant of uncertain significance by one submitter. Due to limited information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of this variant is uncertain at this time. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.17

CADD

Uncertain

DANN

Benign

0.96

DEOGEN2

Benign

0.17

T;T

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

.;D

M_CAP

Uncertain

0.10

MetaRNN

Uncertain

0.72

D;D

MetaSVM

Uncertain

0.75

MutationAssessor

Uncertain

2.4

M;M

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-1.9

.;N

REVEL

Pathogenic

0.68

Sift

Uncertain

0.0040

.;D

Sift4G

Benign

0.15

T;T

Polyphen

0.97

D;D

Vest4

0.73

MutPred

0.41

Loss of MoRF binding (P = 0.01);Loss of MoRF binding (P = 0.01);

MVP

0.93

MPC

0.047

ClinPred

0.91

GERP RS

5.5

Varity_R

0.22

gMVP

0.51

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over