rs45461501

Variant names:

• chr8-60828630-A-G
• rs45461501
• NM_017780.4:c.3379-33A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_017780.4(CHD7):​c.3379-33A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00682 in 1,575,736 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0047 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0070 (32 hom.)
• Consequence: CHD7 NM_017780.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.08
• 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: 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 8-60828630-A-G is Benign according to our data. Variant chr8-60828630-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 260902.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0047 (716/152264) while in subpopulation AMR AF = 0.00909 (139/15294). AF 95% confidence interval is 0.00786. There are 5 homozygotes in GnomAd4. There are 348 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AD,AR gene

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.3379-33A>G		intron	N/A	NP_060250.2
	CHD7	NM_001316690.1		c.1717-33599A>G		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.3379-33A>G		intron	N/A	ENSP00000392028.1	Q9P2D1-1
	CHD7	ENST00000524602.5	TSL:1	c.1717-33599A>G		intron	N/A	ENSP00000437061.1	Q9P2D1-4
	CHD7	ENST00000933299.1		c.3379-33A>G		intron	N/A	ENSP00000603358.1

Frequencies

GnomAD3 genomes AF: 0.00471 AC: 716 AN: 152146 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00910

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00722

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00440 AC: 923 AN: 209898 AF XY: 0.00463

Gnomad AFR exome AF: 0.00125

Gnomad AMR exome AF: 0.00400

Gnomad ASJ exome AF: 0.000121

Gnomad EAS exome AF: 0.0000651

Gnomad FIN exome AF: 0.00119

Gnomad NFE exome AF: 0.00725

Gnomad OTH exome AF: 0.00426

GnomAD4 exome AF: 0.00705 AC: 10030 AN: 1423472 Hom.: 32 Cov.: 30 AF XY: 0.00688 AC XY: 4847 AN XY: 704496

African (AFR) AF: 0.000942 AC: 30 AN: 31842

American (AMR) AF: 0.00353 AC: 132 AN: 37430

Ashkenazi Jewish (ASJ) AF: 0.000527 AC: 13 AN: 24656

East Asian (EAS) AF: 0.00 AC: 0 AN: 39050

South Asian (SAS) AF: 0.00212 AC: 170 AN: 80330

European-Finnish (FIN) AF: 0.00138 AC: 72 AN: 52346

Middle Eastern (MID) AF: 0.00107 AC: 6 AN: 5618

European-Non Finnish (NFE) AF: 0.00840 AC: 9184 AN: 1093412

Other (OTH) AF: 0.00720 AC: 423 AN: 58788

GnomAD4 genome AF: 0.00470 AC: 716 AN: 152264 Hom.: 5 Cov.: 32 AF XY: 0.00467 AC XY: 348 AN XY: 74456

African (AFR) AF: 0.00116 AC: 48 AN: 41556

American (AMR) AF: 0.00909 AC: 139 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4824

European-Finnish (FIN) AF: 0.00123 AC: 13 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00722 AC: 491 AN: 68014

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.00546 Hom.: 0

Bravo AF: 0.00481

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.17
DANN	Benign	0.28
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs45461501; hg19: chr8-61741189;