1-147242803-C-T

Variant names:

• chr1-147242803-C-T
• rs1368853275
• NM_004284.6:c.100C>T

Variant summary

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

The NM_004284.6(CHD1L):​c.100C>T​(p.Gln34*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000178 in 1,124,700 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: 0.0000018 (0 hom.)
• Consequence: CHD1L NM_004284.6 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.879
• Publications: 0 publications found

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]

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

ENSG00000237188 (HGNC:):

ACMG classification

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHD1L	NM_004284.6	MANE Select	c.100C>T	p.Gln34*	stop_gained	Exon 1 of 23	NP_004275.4
	CHD1L	NM_001348454.2		c.100C>T	p.Gln34*	stop_gained	Exon 1 of 18	NP_001335383.1	A0A0A0MRH8
	CHD1L	NM_001256338.3		c.100C>T	p.Gln34*	stop_gained	Exon 1 of 17	NP_001243267.1	Q86WJ1-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHD1L	ENST00000369258.8	TSL:1 MANE Select	c.100C>T	p.Gln34*	stop_gained	Exon 1 of 23	ENSP00000358262.4	Q86WJ1-1
	CHD1L	ENST00000369259.4	TSL:1	c.100C>T	p.Gln34*	stop_gained	Exon 1 of 17	ENSP00000358263.3	Q86WJ1-3
	CHD1L	ENST00000467213.5	TSL:1	n.100C>T		non_coding_transcript_exon	Exon 1 of 21	ENSP00000477985.1	A0A087WTM4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000178 AC: 2 AN: 1124700 Hom.: 0 Cov.: 32 AF XY: 0.00000187 AC XY: 1 AN XY: 534782

African (AFR) AF: 0.00 AC: 0 AN: 24350

American (AMR) AF: 0.00 AC: 0 AN: 11670

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14618

East Asian (EAS) AF: 0.00 AC: 0 AN: 28796

South Asian (SAS) AF: 0.00 AC: 0 AN: 21740

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37494

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4478

European-Non Finnish (NFE) AF: 0.00000214 AC: 2 AN: 936582

Other (OTH) AF: 0.00 AC: 0 AN: 44972

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Benign	0.48	N
PhyloP100		0.88
Vest4		0.39
GERP RS		2.0
PromoterAI		-0.034	Neutral
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		3.3
Mutation Taster		=23/177	disease causing (fs/PTC)

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

Other links and lift over

dbSNP: rs1368853275; hg19: chr1-146714453;