chr8-60743089-G-T

Variant names:

• chr8-60743089-G-T
• rs745476515
• NM_017780.4:c.1657G>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4 BP6_Moderate

The NM_017780.4(CHD7):​c.1657G>T​(p.Val553Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,460,706 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 Benign (★). Synonymous variant affecting the same amino acid position (i.e. V553V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: CHD7 NM_017780.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.69
• 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_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.32645065).
• BP6: Variant 8-60743089-G-T is Benign according to our data. Variant chr8-60743089-G-T is described in ClinVar as Benign. ClinVar VariationId is 572755.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.1657G>T	p.Val553Leu	missense	Exon 2 of 38	NP_060250.2
	CHD7	NM_001316690.1		c.1657G>T	p.Val553Leu	missense	Exon 1 of 5	NP_001303619.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHD7	ENST00000423902.7	TSL:5 MANE Select	c.1657G>T	p.Val553Leu	missense	Exon 2 of 38	ENSP00000392028.1
	CHD7	ENST00000524602.5	TSL:1	c.1657G>T	p.Val553Leu	missense	Exon 1 of 5	ENSP00000437061.1
	CHD7	ENST00000525508.1	TSL:5	c.1657G>T	p.Val553Leu	missense	Exon 1 of 12	ENSP00000436027.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000813 AC: 2 AN: 246064 AF XY: 0.00000748

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1460706 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 726610

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.0000697 AC: 6 AN: 86078

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53180

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111416

Other (OTH) AF: 0.00 AC: 0 AN: 60352

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000826 AC: 1

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

CHARGE syndrome Benign:1

Dec 06, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	0.00030	T
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.33	T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	0.97	L
PhyloP100		7.7
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.63	N
REVEL	Benign	0.18
Sift	Benign	0.063	T
Sift4G	Benign	0.82	T
Polyphen		0.84	P
Vest4		0.55
MutPred		0.20		Loss of relative solvent accessibility (P = 0.0186)
MVP		0.81
MPC		0.13
ClinPred		0.41	T
GERP RS		5.7
Varity_R		0.12
gMVP		0.22
Mutation Taster		=52/48	polymorphism

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: rs745476515; hg19: chr8-61655648;