5-98856633-G-A

Position:

• chr5-98856633-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001270.4(CHD1):​c.4880C>T​(p.Ser1627Phe) 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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHD1 NM_001270.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.67

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0812515).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHD1	NM_001270.4	c.4880C>T	p.Ser1627Phe	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.4880C>T	p.Ser1627Phe	missense_variant	36/36	5	NM_001270.4	ENSP00000483667	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 08, 2022

Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	19
DANN	Benign	0.59
DEOGEN2	Benign	0.067	T;T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.086
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.86	.;D
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.081	T;T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	0.90	N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.46	.;N
REVEL	Benign	0.25
Sift	Benign	0.71	.;T
Sift4G	Benign	0.12	T;T
Polyphen		0.011	B;B
Vest4		0.17
MutPred		0.16		Loss of phosphorylation at S1627 (P = 0.0026);Loss of phosphorylation at S1627 (P = 0.0026);
MVP		0.61
MPC		0.039
ClinPred		0.13	T
GERP RS		3.7
Varity_R		0.053
gMVP		0.32

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

Other links and lift over

dbSNP: rs1748055031; hg19: chr5-98192337;