rs794727423

Variant names:

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

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_Moderate

The NM_017780.4(CHD7):c.5405-17G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The gene CHD7 is a known oncogene (CancerMine: 2 oncogene, 3 driver citations). The gene CHD7 is a cancer driver gene (CancerMine: 2 oncogene, 3 driver citations). 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: 12 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 ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = absent, AC = 0 — absent/extremely rare (O3 moderate [+2])

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	Intron 25 of 37	Prot: NP_060250.2
	CHD7 NM_001316690.1		c.1717-11753G>A	intron	Intron 2 of 4	Prot: NP_001303619.1 UniProt:

CHD7 NM_017780.4

MANE Select

HGVSc / HGVSpc.5405-17G>A

Exon rankIntron 25 of 37

intron

Prot: NP_060250.2

CHD7 NM_001316690.1

HGVSc / HGVSpc.1717-11753G>A

Exon rankIntron 2 of 4

intron

Prot: NP_001303619.1UniProt: Q9P2D1-4

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	CHD7 ENST00000423902.7	TSL:5MANE Select	c.5405-17G>A	intron	Intron 25 of 37	Prot: ENSP00000392028.1 UniProt:
	CHD7 ENST00000524602.5	TSL:1	c.1717-11753G>A	intron	Intron 2 of 4	Prot: ENSP00000437061.1 UniProt:
	CHD7 ENST00000933299.1		c.5405-17G>A	intron	Intron 25 of 37	Prot: ENSP00000603358.1 UniProt:

CHD7 ENST00000423902.7

TSL:5MANE Select

HGVSc / HGVSpc.5405-17G>A

Exon rankIntron 25 of 37

intron

Prot: ENSP00000392028.1UniProt: Q9P2D1-1

CHD7 ENST00000524602.5

TSL:1

HGVSc / HGVSpc.1717-11753G>A

Exon rankIntron 2 of 4

intron

Prot: ENSP00000437061.1UniProt: Q9P2D1-4

CHD7 ENST00000933299.1

HGVSc / HGVSpc.5405-17G>A

Exon rankIntron 25 of 37

intron

Prot: ENSP00000603358.1UniProt: 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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs794727423;

hg19: chr8-61763035;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar