rs794727423

Variant names:

• chr8-60850476-G-A
• rs794727423
• NM_017780.4:c.5405-17G>A

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+12 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 12 classification points (ACMG Germline Pathogenicity v2019). PS3PM2PP3_ModeratePP5_Strong

The NM_017780.4(CHD7):c.5405-17G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000329267: Published functional studies show variant leads to an in-frame insertion of 5 amino acids in a non-repeat region (Vuorela et al., 2007" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CHD7 NM_017780.4 intron
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:15
• Conservation: PhyloP100: 0.687
• Publications: 11 publications found

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]

CHD7 Gene-Disease associations (from GenCC):

• CHARGE syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Broad Center for Mendelian Genomics
• hypogonadotropic hypogonadism 5 with or without anosmia

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• hypogonadotropic hypogonadism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Kallmann syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Omenn syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 12 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV000329267: Published functional studies show variant leads to an in-frame insertion of 5 amino acids in a non-repeat region (Vuorela et al., 2007; Legendre et al., 2018); SCV000579495: Minigene assays confirm the pathogenic effect on splicing mechanism; SCV000742794: Analysis of mRNA from the cells of an affected individual showed that this alteration creates a cryptic splice site resulting in the addition of 15 nucleotides (Vuorela P et al. Genet. Med., 2007 Oct;9:690-4).; SCV003933967: Multiple reports have shown experimental evidence that this variant affects mRNA splicing and activates the alternative 3 splice site (examples: Aref-Eshgh_2018 and Legendre_2018).; SCV002768847: An inframe insertion of 5 amino acids was predicted (p.(His1801_Gly1802insAspGlyHisGlyThr)) (PMID: 29255276)
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (threshold 0.0001) — PM2 moderate.
	PP3Computational evidence supports damaging effect		Splicing predictors (SpliceAI/dbscSNV) support splicing impact — moderate computational evidence (PP3); Splicing verdict: pathogenic (Moderate).; Germline computational verdict: not pathogenic.
	PP5Reputable source reports pathogenic		ClinVar 2-star pathogenic — strong (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s). ClinVar submissions strongly and reliably favor pathogenicity (15/15 total P/LP).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_017780.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHD7	NM_017780.4	MANE Select	c.5405-17G>A		intron	N/A	NP_060250.2
	CHD7	NM_001316690.1		c.1717-11753G>A		intron	N/A	NP_001303619.1	Q9P2D1-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHD7	ENST00000423902.7	TSL:5 MANE Select	c.5405-17G>A		intron	N/A	ENSP00000392028.1	Q9P2D1-1
	CHD7	ENST00000524602.5	TSL:1	c.1717-11753G>A		intron	N/A	ENSP00000437061.1	Q9P2D1-4
	CHD7	ENST00000933299.1		c.5405-17G>A		intron	N/A	ENSP00000603358.1	A0ACI8TQS2

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 4 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 exome Warning	AF: 0.00	AC:0	Hom:0	AN:1441278	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:23458	Cov:

Showing 4 sources

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	not provided (6)
4	-	-	CHARGE syndrome (4)
2	-	-	CHD7-related CHARGE syndrome (2)
1	-	-	CHARGE syndrome;C3552553:Hypogonadotropic hypogonadism 5 with or without anosmia (1)
1	-	-	Hypogonadotropic hypogonadism 5 with or without anosmia (1)
1	-	-	Inborn genetic diseases (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	26
BayesDel_noAF	Benign	-0.54
CADD	Benign	16
DANN	Benign	0.70
GPN-Star LLR	N/A	-3.9
GPN-Star score	N/A	3.9
Mutation Taster	N/A	42/58	disease causing (ClinVar)
PhyloP100	Benign	0.69
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.1

Showing 10 of 10 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
DS_AG_spliceai	Pathogenic	1.0	Position offset: 2
DS_AL_spliceai	Pathogenic	0.96	Position offset: 17
Pangolin (max)	Pathogenic	0.88
Pangolin gain	Pathogenic	0.88	Position offset: 2
Pangolin loss	Pathogenic	0.84	Position offset: 17
SpliceAI score (max)	Pathogenic	1.0	Details are displayed if max score is > 0.2

Showing 6 of 6 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs794727423;

hg19: chr8-61763035;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar