rs1554602588

Positions:

• chr8-60845412-A-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_017780.4(CHD7):​c.5210+3A>G variant causes a splice donor region, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHD7 NM_017780.4 splice_donor_region, intron
• Scores: Splicing: ADA: 0.9794
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.51

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 Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 8-60845412-A-G is Pathogenic according to our data. Variant chr8-60845412-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 547193.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHD7	NM_017780.4	c.5210+3A>G		splice_donor_region_variant, intron_variant		ENST00000423902.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHD7	ENST00000423902.7	c.5210+3A>G		splice_donor_region_variant, intron_variant		5	NM_017780.4	P1
CHD7	ENST00000524602.5	c.1717-16817A>G		intron_variant		1
CHD7	ENST00000695853.1	c.5210+3A>G		splice_donor_region_variant, intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

CHARGE syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Oct 26, 2022	The de novo c.5210+3A>G variant identified in the CHD7 gene has previously been reported in four individuals meeting clinical criteria for CHARGE syndrome [PMID: 21554267, 29178447, 35047002] and it has been deposited in ClinVar [ClinVar ID: 547193] as Pathogenic/Likely Pathogenic. This variant is absent from population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8, All of Us), suggesting it is not a common benign variant in the populations represented in those databases. The c.5210+3A>G variant is located in the donor splice region of exon 23 of this 37-exon gene and is predicted to affect mRNA splicing (Splice AI = 0.45(acceptor loss) and 0.51 (donor loss)) which might result in loss-of-function via exon skipping or intron retention; however, there are no functional studies to support or refute this prediction. Based on available evidence this de novo c.5210+3A>G variant identified in CHD7 is classified here as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	DASA	Feb 05, 2022	This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 547193; PMID: 29178447; 29300383) - PS4. This variant is not present in population databases (rs1554602588; gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. In summary, the currently available evidence indicates that the variant is likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	15
DANN	Benign	0.86

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Pathogenic	0.80
SpliceAI score (max)		0.51		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.51		Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1554602588; hg19: chr8-61757971;