rs148517660

chr8-60865600-G-Achr8-60865600-G-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_017780.4(CHD7):c.8661G>A(p.Pro2887=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000861 in 1,613,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000098 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000085 (0 hom.)
• Consequence: CHD7 NM_017780.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.385

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 8-60865600-G-A is Benign according to our data. Variant chr8-60865600-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 158323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-60865600-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.385 with no splicing effect.
• BS2: High AC in GnomAd at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHD7	NM_017780.4	c.8661G>A	p.Pro2887=	synonymous_variant	38/38	ENST00000423902.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHD7	ENST00000423902.7	c.8661G>A	p.Pro2887=	synonymous_variant	38/38	5	NM_017780.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152190 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000209 AC: 52 AN: 249136 Hom.: 0 AF XY: 0.000207 AC XY: 28 AN XY: 135178

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000230

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000848 AC: 124 AN: 1461654 Hom.: 0 Cov.: 31 AF XY: 0.0000921 AC XY: 67 AN XY: 727100

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.000514

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000936

Gnomad4 NFE exome AF: 0.0000666

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152308 Hom.: 0 Cov.: 33 AF XY: 0.0000671 AC XY: 5 AN XY: 74474

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000106 Hom.: 0

Bravo AF: 0.000106

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 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. -

CHARGE association;C3552553:Hypogonadotropic hypogonadism 5 with or without anosmia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 30, 2021

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 07, 2021

This variant is associated with the following publications: (PMID: 18445044) -

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. -

CHARGE association Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Nov 17, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	6.5
Dann	Benign	0.64
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: rs148517660; hg19: chr8-61778159; COSMIC: COSV101418495; COSMIC: COSV101418495;