1-6106487-A-T

Position:

• chr1-6106487-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_015557.3(CHD5):​c.5765T>A​(p.Met1922Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHD5 NM_015557.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.59

Genes affected

CHD5 (HGNC:16816): (chromodomain helicase DNA binding protein 5) This gene encodes a member of the chromodomain helicase DNA-binding protein family. Members of this family are characterized by a chromodomain, a helicase ATP-binding domain and an additional functional domain. This gene encodes a neuron-specific protein that may function in chromatin remodeling and gene transcription. This gene is a potential tumor suppressor gene that may play a role in the development of neuroblastoma. [provided by RefSeq, Feb 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 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), CHD5. . Gene score misZ 5.3168 (greater than the threshold 3.09). Trascript score misZ 5.6838 (greater than threshold 3.09). GenCC has associacion of gene with schizophrenia, parenti-mignot neurodevelopmental syndrome.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHD5	NM_015557.3	c.5765T>A	p.Met1922Lys	missense_variant	40/42	ENST00000262450.8	NP_056372.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHD5	ENST00000262450.8	c.5765T>A	p.Met1922Lys	missense_variant	40/42	1	NM_015557.3	ENSP00000262450	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

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

Labcorp Genetics (formerly Invitae), Labcorp

Apr 28, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant  is likely to be tolerated. This variant has not been reported in the literature in individuals affected with CHD5-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 1922 of the CHD5 protein (p.Met1922Lys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Uncertain	0.083	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.065	T
Eigen	Benign	-0.088
Eigen_PC	Benign	0.079
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.097	D
MetaRNN	Uncertain	0.50	T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	0.97	D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.42
Sift	Benign	0.10	T
Sift4G	Benign	0.95	T
Polyphen		0.16	B
Vest4		0.79
MutPred		0.36		Gain of ubiquitination at M1922 (P = 0.0082);
MVP		0.56
MPC		1.3
ClinPred		0.64	D
GERP RS		4.9
Varity_R		0.60
gMVP		0.84

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-6166547;