rs114996731

Variant names:

• chr8-60841631-T-G
• rs114996731
• NM_017780.4:c.4534-13T>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_017780.4(CHD7):​c.4534-13T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00182 in 1,597,992 control chromosomes in the GnomAD database, including 51 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.010 (28 hom., cov: 33)
  • Exomes 𝑓: 0.00094 (23 hom.)
• Consequence: CHD7 NM_017780.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 1.23
• Publications: 1 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 8-60841631-T-G is Benign according to our data. Variant chr8-60841631-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 158297.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0101 (1543/152324) while in subpopulation AFR AF = 0.0351 (1460/41562). AF 95% confidence interval is 0.0336. There are 28 homozygotes in GnomAd4. There are 707 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 28 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.4534-13T>G		intron	N/A	NP_060250.2
	CHD7	NM_001316690.1		c.1717-20598T>G		intron	N/A	NP_001303619.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHD7	ENST00000423902.7	TSL:5 MANE Select	c.4534-13T>G		intron	N/A	ENSP00000392028.1
	CHD7	ENST00000524602.5	TSL:1	c.1717-20598T>G		intron	N/A	ENSP00000437061.1
	CHD7	ENST00000933299.1		c.4534-13T>G		intron	N/A	ENSP00000603358.1

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1543 AN: 152206 Hom.: 28 Cov.: 33

Gnomad AFR AF: 0.0352

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00399

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00621

GnomAD2 exomes AF: 0.00259 AC: 646 AN: 249066 AF XY: 0.00190

Gnomad AFR exome AF: 0.0372

Gnomad AMR exome AF: 0.00160

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000708

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.000939 AC: 1358 AN: 1445668 Hom.: 23 Cov.: 29 AF XY: 0.000798 AC XY: 572 AN XY: 716650

African (AFR) AF: 0.0344 AC: 1142 AN: 33198

American (AMR) AF: 0.00193 AC: 86 AN: 44572

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26034

East Asian (EAS) AF: 0.00 AC: 0 AN: 39298

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85956

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53300

Middle Eastern (MID) AF: 0.000349 AC: 2 AN: 5726

European-Non Finnish (NFE) AF: 0.0000200 AC: 22 AN: 1097980

Other (OTH) AF: 0.00176 AC: 105 AN: 59604

GnomAD4 genome AF: 0.0101 AC: 1543 AN: 152324 Hom.: 28 Cov.: 33 AF XY: 0.00949 AC XY: 707 AN XY: 74490

African (AFR) AF: 0.0351 AC: 1460 AN: 41562

American (AMR) AF: 0.00399 AC: 61 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68036

Other (OTH) AF: 0.00614 AC: 13 AN: 2116

Alfa AF: 0.00747 Hom.: 11

Bravo AF: 0.0117

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	1	1	CHARGE syndrome (2)
-	-	2	not provided (2)
-	-	1	Hypogonadotropic hypogonadism 5 with or without anosmia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	15
DANN	Benign	0.65
PhyloP100		1.2
Mutation Taster		=100/0	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: rs114996731; hg19: chr8-61754190;