Genetic Variant CHD1:p.Arg460Thr (chr5-98897307-C-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PM5PP3_Moderate

The NM_001270.4(CHD1):c.1379G>C(p.Arg460Thr) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R460K) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

CHD1
NM_001270.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.54

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

Pilarowski-Bjornsson syndrome
Inheritance: AD, Unknown Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
complex neurodevelopmental disorder
Inheritance: AR, AD Classification: LIMITED Submitted by: Ambry Genetics, ClinGen

CHD1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr5-98897307-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 438821.Status of the report is no_assertion_criteria_provided, 0 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.864

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001270.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CHD1	NM_001270.4	MANE Select	c.1379G>C	p.Arg460Thr	missense	Exon 11 of 36	NP_001261.2	O14646-1
CHD1	NM_001364113.3		c.1379G>C	p.Arg460Thr	missense	Exon 11 of 37	NP_001351042.1	A0A087WVF4
CHD1	NM_001376194.2		c.1379G>C	p.Arg460Thr	missense	Exon 11 of 36	NP_001363123.1	O14646-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CHD1	ENST00000614616.5	TSL:5 MANE Select	c.1379G>C	p.Arg460Thr	missense	Exon 11 of 36	ENSP00000483667.1	O14646-1
CHD1	ENST00000511067.3	TSL:5	c.1379G>C	p.Arg460Thr	missense	Exon 11 of 37	ENSP00000479403.2	A0A087WVF4
CHD1	ENST00000926040.1		c.1379G>C	p.Arg460Thr	missense	Exon 11 of 36	ENSP00000596099.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.44

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.36

MetaRNN

Pathogenic

0.86

MetaSVM

Pathogenic

0.98

MutationAssessor

Uncertain

2.9

PhyloP100

7.5

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-5.5

REVEL

Pathogenic

0.83

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.78

MutPred

0.48

Loss of MoRF binding (P = 0.034)

MVP

0.95

MPC

2.4

ClinPred

1.0

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.52

gMVP

0.81

Mutation Taster

=33/67

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over