Genetic Variant CHD1L:p.Gln38* (chr1-147242815-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004284.6(CHD1L):c.112C>T(p.Gln38*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000888 in 1,125,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 8.9e-7 ( 0 hom. )

Consequence

CHD1L
NM_004284.6 stop_gained

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.437

Publications

0 publications found

Variant links:

Genes affected

CHD1L (HGNC:1916): (chromodomain helicase DNA binding protein 1 like) This gene encodes a DNA helicase protein involved in DNA repair. The protein converts ATP to add poly(ADP-ribose) as it regulates chromatin relaxation following DNA damage. Overexpression of this gene has been linked to several types of cancers. [provided by RefSeq, Feb 2017]

CHD1L links:

FMO5 (HGNC:3773): (flavin containing dimethylaniline monoxygenase 5) Metabolic N-oxidation of the diet-derived amino-trimethylamine (TMA) is mediated by flavin-containing monooxygenase and is subject to an inherited FMO3 polymorphism in man resulting in a small subpopulation with reduced TMA N-oxidation capacity resulting in fish odor syndrome Trimethylaminuria. Three forms of the enzyme, FMO1 found in fetal liver, FMO2 found in adult liver, and FMO3 are encoded by genes clustered in the 1q23-q25 region. Flavin-containing monooxygenases are NADPH-dependent flavoenzymes that catalyzes the oxidation of soft nucleophilic heteroatom centers in drugs, pesticides, and xenobiotics. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2009]

FMO5 Gene-Disease associations (from GenCC):

congenital heart disease
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

FMO5 links:

ENSG00000237188 (HGNC:):

ENSG00000237188 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004284.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CHD1L	NM_004284.6	MANE Select	c.112C>T	p.Gln38*	stop_gained	Exon 1 of 23	NP_004275.4
CHD1L	NM_001348454.2		c.112C>T	p.Gln38*	stop_gained	Exon 1 of 18	NP_001335383.1	A0A0A0MRH8
CHD1L	NM_001256338.3		c.112C>T	p.Gln38*	stop_gained	Exon 1 of 17	NP_001243267.1	Q86WJ1-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CHD1L	ENST00000369258.8	TSL:1 MANE Select	c.112C>T	p.Gln38*	stop_gained	Exon 1 of 23	ENSP00000358262.4	Q86WJ1-1
CHD1L	ENST00000369259.4	TSL:1	c.112C>T	p.Gln38*	stop_gained	Exon 1 of 17	ENSP00000358263.3	Q86WJ1-3
CHD1L	ENST00000467213.5	TSL:1	n.112C>T		non_coding_transcript_exon	Exon 1 of 21	ENSP00000477985.1	A0A087WTM4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.88e-7

AC:

AN:

1125858

Hom.:

Cov.:

AF XY:

0.00000187

AC XY:

AN XY:

535536

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

24378

American (AMR)

AF:

0.00

AC:

AN:

11798

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14636

East Asian (EAS)

AF:

0.00

AC:

AN:

28846

South Asian (SAS)

AF:

0.00

AC:

AN:

21836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4464

European-Non Finnish (NFE)

AF:

0.00000107

AC:

AN:

937498

Other (OTH)

AF:

0.00

AC:

AN:

44986

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.23

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Benign

-0.026

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.045

PhyloP100

0.44

Vest4

0.54

GERP RS

-0.40

PromoterAI

-0.078

Neutral

(source)

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.2

Mutation Taster

=29/171

disease causing (fs/PTC)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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