5-98856721-A-G

Position:

• chr5-98856721-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001270.4(CHD1):​c.4792T>C​(p.Tyr1598His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 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: 8.25

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, CHD1
• BP4: Computational evidence support a benign effect (MetaRNN=0.34375805).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHD1	NM_001270.4	c.4792T>C	p.Tyr1598His	missense_variant	36/36	ENST00000614616.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHD1	ENST00000614616.5	c.4792T>C	p.Tyr1598His	missense_variant	36/36	5	NM_001270.4	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Pilarowski-Bjornsson syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 26, 2020

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.082	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	19
DANN	Benign	0.92
DEOGEN2	Benign	0.039	T;T
Eigen	Benign	-0.0089
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.34	T;T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.76	T
Sift4G	Benign	0.57	T;T
Polyphen		0.0030	B;B
Vest4		0.69
MutPred		0.20		Gain of loop (P = 0.0166);Gain of loop (P = 0.0166);
MVP		0.67
MPC		0.043
ClinPred		0.41	T
GERP RS		5.7
Varity_R		0.059
gMVP		0.41

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: rs1748060837; hg19: chr5-98192425;