rs114996731

Positions:

• chr8-60841631-T-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_017780.4(CHD7):​c.4534-13T>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00182 in 1,597,992 control chromosomes in the GnomAD database, including 51 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 0.010 (28 hom., cov: 33)
  • Exomes 𝑓: 0.00094 (23 hom.)
• Consequence: CHD7 NM_017780.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 1.23

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 8-60841631-T-G is Benign according to our data. Variant chr8-60841631-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 158297.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=6}. Variant chr8-60841631-T-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0101 (1543/152324) while in subpopulation AFR AF= 0.0351 (1460/41562). AF 95% confidence interval is 0.0336. There are 28 homozygotes in gnomad4. There are 707 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1543 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHD7	NM_017780.4	c.4534-13T>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000423902.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHD7	ENST00000423902.7	c.4534-13T>G		splice_polypyrimidine_tract_variant, intron_variant		5	NM_017780.4	P1
CHD7	ENST00000524602.5	c.1717-20598T>G		intron_variant		1
CHD7	ENST00000695853.1	c.4534-13T>G		splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1543 AN: 152206 Hom.: 28 Cov.: 33

Gnomad AFR AF: 0.0352

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00259 AC: 646 AN: 249066 Hom.: 12 AF XY: 0.00190 AC XY: 257 AN XY: 135132

Gnomad AFR exome AF: 0.0372

Gnomad AMR exome AF: 0.00160

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000708

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.000939 AC: 1358 AN: 1445668 Hom.: 23 Cov.: 29 AF XY: 0.000798 AC XY: 572 AN XY: 716650

Gnomad4 AFR exome AF: 0.0344

Gnomad4 AMR exome AF: 0.00193

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000200

Gnomad4 OTH exome AF: 0.00176

GnomAD4 genome AF: 0.0101 AC: 1543 AN: 152324 Hom.: 28 Cov.: 33 AF XY: 0.00949 AC XY: 707 AN XY: 74490

Gnomad4 AFR AF: 0.0351

Gnomad4 AMR AF: 0.00399

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00614

Alfa AF: 0.00593 Hom.: 5

Bravo AF: 0.0117

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 28, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 23, 2017	c.4534-13T>G in intron 19 of CHD7: This variant is not expected to have clinical significance because it has been identified in 3.79% (370/9758) of African chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs114996731). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

CHARGE syndrome Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 11, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Hypogonadotropic hypogonadism 5 with or without anosmia Benign:1

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	15
DANN	Benign	0.65

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: rs114996731; hg19: chr8-61754190;