1-147242739-A-C

Variant names:

• chr1-147242739-A-C
• rs587765929
• NM_004284.6:c.36A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004284.6(CHD1L):​c.36A>C​(p.Gln12His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000901 in 1,109,918 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q12R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 9.0e-7 (0 hom.)
• Consequence: CHD1L NM_004284.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.967
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.062033743).

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.36A>C	p.Gln12His	missense	Exon 1 of 23	NP_004275.4
	CHD1L	NM_001348454.2		c.36A>C	p.Gln12His	missense	Exon 1 of 18	NP_001335383.1	A0A0A0MRH8
	CHD1L	NM_001256338.3		c.36A>C	p.Gln12His	missense	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.36A>C	p.Gln12His	missense	Exon 1 of 23	ENSP00000358262.4	Q86WJ1-1
	CHD1L	ENST00000369259.4	TSL:1	c.36A>C	p.Gln12His	missense	Exon 1 of 17	ENSP00000358263.3	Q86WJ1-3
	CHD1L	ENST00000467213.5	TSL:1	n.36A>C		non_coding_transcript_exon	Exon 1 of 21	ENSP00000477985.1	A0A087WTM4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000296 AC: 1 AN: 33834 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000615

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.01e-7 AC: 1 AN: 1109918 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 526278

African (AFR) AF: 0.00 AC: 0 AN: 23866

American (AMR) AF: 0.00 AC: 0 AN: 10338

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14486

East Asian (EAS) AF: 0.00 AC: 0 AN: 27710

South Asian (SAS) AF: 0.00 AC: 0 AN: 20916

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3940

European-Non Finnish (NFE) AF: 0.00000108 AC: 1 AN: 929604

Other (OTH) AF: 0.00 AC: 0 AN: 44478

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000964 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	2.0
DANN	Benign	0.74
DEOGEN2	Benign	0.0096	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0029	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.062	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.97
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.17	N
REVEL	Benign	0.16
Sift	Benign	0.22	T
Sift4G	Benign	0.18	T
Polyphen		0.0	B
Vest4		0.14
MutPred		0.27		Gain of glycosylation at S8 (P = 0.0871)
MVP		0.15
MPC		0.037
ClinPred		0.044	T
GERP RS		-1.1
PromoterAI		0.022	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.032
gMVP		0.41
Mutation Taster		=297/3	polymorphism

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

Other links and lift over

dbSNP: rs587765929; hg19: chr1-146714389;