5-98856537-C-G

Position:

• chr5-98856537-C-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2 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
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.16

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CHD1. . Trascript score misZ 3.2778 (greater than threshold 3.09). GenCC has associacion of gene with Pilarowski-Bjornsson syndrome.
• BS2: High AC in GnomAdExome4 at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHD1	NM_001270.4	c.4976G>C	p.Arg1659Thr	missense_variant	36/36	ENST00000614616.5	NP_001261.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHD1	ENST00000614616.5	c.4976G>C	p.Arg1659Thr	missense_variant	36/36	5	NM_001270.4	ENSP00000483667	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000157 AC: 23 AN: 1461656 Hom.: 0 Cov.: 33 AF XY: 0.0000110 AC XY: 8 AN XY: 727108

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.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pilarowski-Bjornsson syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genomics Laboratory, Washington University in St. Louis	Aug 25, 2023	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Jun 04, 2021	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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.17
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Benign	0.17	T;T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	.;D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.72	D;D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Uncertain	2.4	M;M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.80	D
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	D
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.

Other links and lift over

hg19: chr5-98192241;