NM_017780.4:c.5405-7G>A

Variant names:

• chr8-60850486-G-A
• rs398124321
• NM_017780.4:c.5405-7G>A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3 PM2 PP5_Very_Strong

The NM_017780.4(CHD7):​c.5405-7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,449,966 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 Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000329268: Published in vitro splicing assay and RT-PCR studies indicate this variant creates a new splice acceptor site in intron 25 that results in abnormal gene splicing resulting in a frameshift in the resultant product (Song et al., 2011" and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CHD7 NM_017780.4 splice_region, intron
• Scores: Splicing: ADA: 0.9358
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:20
• Conservation: PhyloP100: 0.922
• 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, G2P, Labcorp Genetics (formerly Invitae), Broad Center for Mendelian Genomics, ClinGen
• 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

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000329268: Published in vitro splicing assay and RT-PCR studies indicate this variant creates a new splice acceptor site in intron 25 that results in abnormal gene splicing resulting in a frameshift in the resultant product (Song et al., 2011; Legendre et al., 2018); SCV000552237: Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 21931733).; SCV000919211: Two independent mini-gene assays confirm the impact on splicing, specificaly the introduction of a 5-bp intronic sequence by activation of a cryptic acceptor site leading to a frameshift mutation (Legendre_2018, Song_2011).; SCV002572741: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 21931733).; SCV001164433: "In vitro functional studies provide some evidence that the c.5405-7G>A variant may impact protein function by causing a five base pair insertion during in vitro splicing." PMID:21931733; SCV001443871: An in vitro splicing analysis demonstrated the introduction of 5 additional nucleotides due to the activation of a cryptic acceptor site (Song, 2011).; SCV004116098: Functional studies found it creates a frameshift and premature protein termination by activating a cryptic splice acceptor site and introducing a five-base pair intronic sequence to the CHD7 messenger RNA (Song et al. 2011. PubMed ID: 21931733; Legendre et al. 2018. PubMed ID: 29255276).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-60850486-G-A is Pathogenic according to our data. Variant chr8-60850486-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 95795.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHD7	NM_017780.4	MANE Select	c.5405-7G>A		splice_region intron	N/A	NP_060250.2
	CHD7	NM_001316690.1		c.1717-11743G>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.5405-7G>A		splice_region intron	N/A	ENSP00000392028.1	Q9P2D1-1
	CHD7	ENST00000524602.5	TSL:1	c.1717-11743G>A		intron	N/A	ENSP00000437061.1	Q9P2D1-4
	CHD7	ENST00000933299.1		c.5405-7G>A		splice_region intron	N/A	ENSP00000603358.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1449966 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 718616

African (AFR) AF: 0.00 AC: 0 AN: 33282

American (AMR) AF: 0.00 AC: 0 AN: 44500

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26028

East Asian (EAS) AF: 0.00 AC: 0 AN: 39330

South Asian (SAS) AF: 0.00 AC: 0 AN: 85920

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53276

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.00000272 AC: 3 AN: 1102048

Other (OTH) AF: 0.00 AC: 0 AN: 59848

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
11	-	-	CHARGE syndrome (11)
6	-	-	not provided (6)
1	-	-	CHD7-related disorder (1)
1	-	-	Hypogonadotropic hypogonadism 5 with or without anosmia (1)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	22
DANN	Benign	0.81
PhyloP100		0.92
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=32/68	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.94
Splicevardb		3.0
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.98		Position offset: 2
DS_AL_spliceai		0.20		Position offset: 7

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

Other links and lift over

dbSNP: rs398124321; hg19: chr8-61763045; COSMIC: COSV101418202; COSMIC: COSV101418202;