rs3763592

Variant names:

• chr8-60852714-C-T
• rs3763592
• NM_017780.4:c.6103+8C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_017780.4(CHD7):​c.6103+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0572 in 1,613,390 control chromosomes in the GnomAD database, including 7,029 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (3121 hom., cov: 32)
  • Exomes 𝑓: 0.049 (3908 hom.)
• Consequence: CHD7 NM_017780.4 splice_region, intron
• Scores: Splicing: ADA: 0.00002795
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.0930
• Publications: 10 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=-0.83).
• BP6: Variant 8-60852714-C-T is Benign according to our data. Variant chr8-60852714-C-T is described in ClinVar as Benign. ClinVar VariationId is 95799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.368 is higher than 0.05.

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.6103+8C>T		splice_region intron	N/A	NP_060250.2
	CHD7	NM_001316690.1		c.1717-9515C>T		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.6103+8C>T		splice_region intron	N/A	ENSP00000392028.1	Q9P2D1-1
	CHD7	ENST00000524602.5	TSL:1	c.1717-9515C>T		intron	N/A	ENSP00000437061.1	Q9P2D1-4
	CHD7	ENST00000933299.1		c.6139+8C>T		splice_region intron	N/A	ENSP00000603358.1

Frequencies

GnomAD3 genomes AF: 0.138 AC: 20950 AN: 151966 Hom.: 3120 Cov.: 32

Gnomad AFR AF: 0.374

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0711

Gnomad ASJ AF: 0.0688

Gnomad EAS AF: 0.0164

Gnomad SAS AF: 0.0478

Gnomad FIN AF: 0.0757

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0411

Gnomad OTH AF: 0.120

GnomAD2 exomes AF: 0.0662 AC: 16489 AN: 249032 AF XY: 0.0611

Gnomad AFR exome AF: 0.386

Gnomad AMR exome AF: 0.0398

Gnomad ASJ exome AF: 0.0749

Gnomad EAS exome AF: 0.0132

Gnomad FIN exome AF: 0.0806

Gnomad NFE exome AF: 0.0411

Gnomad OTH exome AF: 0.0589

GnomAD4 exome AF: 0.0488 AC: 71363 AN: 1461306 Hom.: 3908 Cov.: 32 AF XY: 0.0476 AC XY: 34633 AN XY: 726954

African (AFR) AF: 0.385 AC: 12883 AN: 33452

American (AMR) AF: 0.0446 AC: 1996 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0755 AC: 1972 AN: 26132

East Asian (EAS) AF: 0.0166 AC: 657 AN: 39694

South Asian (SAS) AF: 0.0475 AC: 4099 AN: 86250

European-Finnish (FIN) AF: 0.0783 AC: 4180 AN: 53370

Middle Eastern (MID) AF: 0.0740 AC: 427 AN: 5768

European-Non Finnish (NFE) AF: 0.0371 AC: 41265 AN: 1111558

Other (OTH) AF: 0.0643 AC: 3884 AN: 60368

GnomAD4 genome AF: 0.138 AC: 20973 AN: 152084 Hom.: 3121 Cov.: 32 AF XY: 0.137 AC XY: 10165 AN XY: 74350

African (AFR) AF: 0.373 AC: 15458 AN: 41430

American (AMR) AF: 0.0710 AC: 1086 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0688 AC: 239 AN: 3472

East Asian (EAS) AF: 0.0162 AC: 84 AN: 5176

South Asian (SAS) AF: 0.0473 AC: 228 AN: 4824

European-Finnish (FIN) AF: 0.0757 AC: 801 AN: 10580

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.0410 AC: 2790 AN: 67986

Other (OTH) AF: 0.119 AC: 251 AN: 2114

Alfa AF: 0.0705 Hom.: 4083

Bravo AF: 0.145

Asia WGS AF: 0.0490 AC: 172 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	3	not provided (3)
-	-	1	CHARGE syndrome (1)
-	-	1	Hypogonadotropic hypogonadism 5 with or without anosmia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.1
DANN	Benign	0.55
PhyloP100		-0.093
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000028
dbscSNV1_RF	Benign	0.0
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: rs3763592; hg19: chr8-61765273;