8-60683112-T-C

Variant names:

• chr8-60683112-T-C
• rs4738813
• NM_017780.4:c.-175+4030T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_017780.4(CHD7):​c.-175+4030T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.494 in 152,198 control chromosomes in the GnomAD database, including 22,843 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.49 (22843 hom., cov: 32)
• Consequence: CHD7 NM_017780.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.814
• 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: 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.731 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHD7	NM_017780.4	c.-175+4030T>C		intron_variant	Intron 1 of 37	ENST00000423902.7	NP_060250.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHD7	ENST00000423902.7	c.-175+4030T>C		intron_variant	Intron 1 of 37	5	NM_017780.4	ENSP00000392028.1

Frequencies

GnomAD3 genomes AF: 0.495 AC: 75239 AN: 152080 Hom.: 22842 Cov.: 32

Gnomad AFR AF: 0.124

Gnomad AMI AF: 0.644

Gnomad AMR AF: 0.600

Gnomad ASJ AF: 0.585

Gnomad EAS AF: 0.749

Gnomad SAS AF: 0.723

Gnomad FIN AF: 0.677

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.626

Gnomad OTH AF: 0.505

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.494 AC: 75251 AN: 152198 Hom.: 22843 Cov.: 32 AF XY: 0.506 AC XY: 37641 AN XY: 74410

African (AFR) AF: 0.124 AC: 5159 AN: 41554

American (AMR) AF: 0.600 AC: 9181 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.585 AC: 2031 AN: 3472

East Asian (EAS) AF: 0.751 AC: 3893 AN: 5186

South Asian (SAS) AF: 0.724 AC: 3494 AN: 4826

European-Finnish (FIN) AF: 0.677 AC: 7165 AN: 10578

Middle Eastern (MID) AF: 0.463 AC: 136 AN: 294

European-Non Finnish (NFE) AF: 0.626 AC: 42534 AN: 67968

Other (OTH) AF: 0.506 AC: 1071 AN: 2116

Alfa AF: 0.578 Hom.: 15828

Bravo AF: 0.469

Asia WGS AF: 0.671 AC: 2329 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	11
DANN	Benign	0.67
PhyloP100		0.81
Mutation Taster		=100/0	polymorphism (auto)

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: rs4738813; hg19: chr8-61595671;