rs41265246

chr8-60838159-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS2

The NM_017780.4(CHD7):c.4437G>A(p.Gly1479=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000456 in 1,563,238 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00047 (2 hom.)
• Consequence: CHD7 NM_017780.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -0.121

Genes affected

CHD7 (HGNC:20626): (chromodomain helicase DNA binding protein 7) This gene encodes a protein that contains several helicase family domains. Mutations in this gene have been found in some patients with the CHARGE syndrome. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 8-60838159-G-A is Benign according to our data. Variant chr8-60838159-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 95790.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=2, Likely_benign=3}. Variant chr8-60838159-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.121 with no splicing effect.
• BS2: High AC in GnomAd at 46 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHD7	NM_017780.4	c.4437G>A	p.Gly1479=	synonymous_variant	19/38	ENST00000423902.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHD7	ENST00000423902.7	c.4437G>A	p.Gly1479=	synonymous_variant	19/38	5	NM_017780.4	P1
CHD7	ENST00000524602.5	c.1717-24070G>A		intron_variant		1
CHD7	ENST00000695853.1	c.4437G>A	p.Gly1479=	synonymous_variant, NMD_transcript_variant	19/37

Frequencies

GnomAD3 genomes AF: 0.000303 AC: 46 AN: 152064 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000515

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000397 AC: 78 AN: 196358 Hom.: 0 AF XY: 0.000451 AC XY: 47 AN XY: 104298

Gnomad AFR exome AF: 0.0000838

Gnomad AMR exome AF: 0.000214

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000647

Gnomad FIN exome AF: 0.0000537

Gnomad NFE exome AF: 0.000614

Gnomad OTH exome AF: 0.000386

GnomAD4 exome AF: 0.000473 AC: 667 AN: 1411056 Hom.: 2 Cov.: 31 AF XY: 0.000505 AC XY: 353 AN XY: 698774

Gnomad4 AFR exome AF: 0.0000921

Gnomad4 AMR exome AF: 0.000233

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000483

Gnomad4 FIN exome AF: 0.0000975

Gnomad4 NFE exome AF: 0.000542

Gnomad4 OTH exome AF: 0.000426

GnomAD4 genome AF: 0.000302 AC: 46 AN: 152182 Hom.: 0 Cov.: 32 AF XY: 0.000255 AC XY: 19 AN XY: 74402

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.000515

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000343 Hom.: 0

Bravo AF: 0.000374

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 15, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 18, 2020	This variant is associated with the following publications: (PMID: 30733481) -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

CHARGE syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 27, 2023

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 18, 2018

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Hypogonadotropic hypogonadism 5 with or without anosmia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
Cadd	Benign	3.9
Dann	Benign	0.66
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs41265246; hg19: chr8-61750718;