8-60850514-T-G

Variant names:

• chr8-60850514-T-G
• rs1554603550
• NM_017780.4:c.5426T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Moderate PP5_Moderate

The NM_017780.4(CHD7):​c.5426T>G​(p.Met1809Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1809T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHD7 NM_017780.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 8.02
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia, Broad Center for Mendelian Genomics, ClinGen, G2P
• 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 11 uncertain in NM_017780.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.901
• PP5: Variant 8-60850514-T-G is Pathogenic according to our data. Variant chr8-60850514-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 521017.Status of the report is criteria_provided_single_submitter, 1 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHD7	NM_017780.4	MANE Select	c.5426T>G	p.Met1809Arg	missense	Exon 26 of 38	NP_060250.2
	CHD7	NM_001316690.1		c.1717-11715T>G		intron	N/A	NP_001303619.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHD7	ENST00000423902.7	TSL:5 MANE Select	c.5426T>G	p.Met1809Arg	missense	Exon 26 of 38	ENSP00000392028.1
	CHD7	ENST00000524602.5	TSL:1	c.1717-11715T>G		intron	N/A	ENSP00000437061.1
	CHD7	ENST00000695853.1		n.5426T>G		non_coding_transcript_exon	Exon 26 of 37	ENSP00000512218.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Mar 18, 2016

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CHARGE syndrome Uncertain:1

Dec 20, 2024

3billion

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v4.1.0 dataset. Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.93 (>=0.6, sensitivity 0.68 and specificity 0.92)]. The same nucleotide change resulting in the same amino acid change has been previously reported to be associated with CHD7-related disorder (ClinVar ID: VCV000521017). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.78	D
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		8.0
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.99	D
Vest4		0.93
MutPred		0.58		Gain of solvent accessibility (P = 0.0171)
MVP		0.98
MPC		1.4
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.96
gMVP		0.96
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1554603550; hg19: chr8-61763073;