chr1-147242777-G-C

Position:

• chr1-147242777-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004284.6(CHD1L):​c.74G>C​(p.Arg25Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0914 in 1,269,940 control chromosomes in the GnomAD database, including 5,842 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.092 (722 hom., cov: 33)
  • Exomes 𝑓: 0.091 (5120 hom.)
• Consequence: CHD1L NM_004284.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.773

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]

ENSG00000237188 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018559396).
• BP6: Variant 1-147242777-G-C is Benign according to our data. Variant chr1-147242777-G-C is described in ClinVar as [Benign]. Clinvar id is 1260082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.149 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHD1L	NM_004284.6	c.74G>C	p.Arg25Pro	missense_variant	1/23	ENST00000369258.8	NP_004275.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHD1L	ENST00000369258.8	c.74G>C	p.Arg25Pro	missense_variant	1/23	1	NM_004284.6	ENSP00000358262.4

Frequencies

GnomAD3 genomes AF: 0.0922 AC: 14027 AN: 152100 Hom.: 717 Cov.: 33

Gnomad AFR AF: 0.0736

Gnomad AMI AF: 0.0571

Gnomad AMR AF: 0.110

Gnomad ASJ AF: 0.0582

Gnomad EAS AF: 0.158

Gnomad SAS AF: 0.144

Gnomad FIN AF: 0.124

Gnomad MID AF: 0.0892

Gnomad NFE AF: 0.0883

Gnomad OTH AF: 0.0880

GnomAD3 exomes AF: 0.120 AC: 5269 AN: 43920 Hom.: 329 AF XY: 0.120 AC XY: 2710 AN XY: 22556

Gnomad AFR exome AF: 0.0740

Gnomad AMR exome AF: 0.159

Gnomad ASJ exome AF: 0.0853

Gnomad EAS exome AF: 0.197

Gnomad SAS exome AF: 0.171

Gnomad FIN exome AF: 0.126

Gnomad NFE exome AF: 0.104

Gnomad OTH exome AF: 0.112

GnomAD4 exome AF: 0.0912 AC: 101986 AN: 1117732 Hom.: 5120 Cov.: 33 AF XY: 0.0915 AC XY: 48522 AN XY: 530552

Gnomad4 AFR exome AF: 0.0736

Gnomad4 AMR exome AF: 0.128

Gnomad4 ASJ exome AF: 0.0692

Gnomad4 EAS exome AF: 0.213

Gnomad4 SAS exome AF: 0.140

Gnomad4 FIN exome AF: 0.126

Gnomad4 NFE exome AF: 0.0855

Gnomad4 OTH exome AF: 0.0944

GnomAD4 genome AF: 0.0922 AC: 14039 AN: 152208 Hom.: 722 Cov.: 33 AF XY: 0.0948 AC XY: 7053 AN XY: 74418

Gnomad4 AFR AF: 0.0735

Gnomad4 AMR AF: 0.110

Gnomad4 ASJ AF: 0.0582

Gnomad4 EAS AF: 0.158

Gnomad4 SAS AF: 0.145

Gnomad4 FIN AF: 0.124

Gnomad4 NFE AF: 0.0883

Gnomad4 OTH AF: 0.0889

Alfa AF: 0.0414 Hom.: 34

Bravo AF: 0.0896

TwinsUK AF: 0.0839 AC: 311

ALSPAC AF: 0.0820 AC: 316

ESP6500AA AF: 0.0675 AC: 284

ESP6500EA AF: 0.0780 AC: 652

ExAC AF: 0.0821 AC: 8833

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	18
DANN	Benign	0.71
DEOGEN2	Benign	0.016	T;.
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.072	N
LIST_S2	Benign	0.51	T;T
MetaRNN	Benign	0.0019	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.0	L;L
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.71	N;N
REVEL	Benign	0.29
Sift	Benign	0.094	T;T
Sift4G	Benign	0.083	T;T
Polyphen		0.0	B;B
Vest4		0.055
MPC		0.12
ClinPred		0.033	T
GERP RS		3.1
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.2
Varity_R		0.21
gMVP		0.53

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: rs11588753; hg19: chr1-146714427; COSMIC: COSV100787343;