NM_017780.4:c.2238+39G>A

Variant names:

• chr8-60795166-G-A
• rs4540437
• NM_017780.4:c.2238+39G>A

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.2238+39G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.793 in 1,598,936 control chromosomes in the GnomAD database, including 505,823 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.84 (53860 hom., cov: 30)
  • Exomes 𝑓: 0.79 (451963 hom.)
• Consequence: CHD7 NM_017780.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.215
• Publications: 19 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 8-60795166-G-A is Benign according to our data. Variant chr8-60795166-G-A is described in ClinVar as Benign. ClinVar VariationId is 158325.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.925 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.2238+39G>A		intron	N/A	NP_060250.2
	CHD7	NM_001316690.1		c.1716+14116G>A		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.2238+39G>A		intron	N/A	ENSP00000392028.1	Q9P2D1-1
	CHD7	ENST00000524602.5	TSL:1	c.1716+14116G>A		intron	N/A	ENSP00000437061.1	Q9P2D1-4
	CHD7	ENST00000933299.1		c.2238+39G>A		intron	N/A	ENSP00000603358.1

Frequencies

GnomAD3 genomes AF: 0.838 AC: 127419 AN: 152032 Hom.: 53814 Cov.: 30

Gnomad AFR AF: 0.932

Gnomad AMI AF: 0.731

Gnomad AMR AF: 0.829

Gnomad ASJ AF: 0.764

Gnomad EAS AF: 0.943

Gnomad SAS AF: 0.918

Gnomad FIN AF: 0.832

Gnomad MID AF: 0.769

Gnomad NFE AF: 0.776

Gnomad OTH AF: 0.814

GnomAD2 exomes AF: 0.829 AC: 199676 AN: 240904 AF XY: 0.828

Gnomad AFR exome AF: 0.939

Gnomad AMR exome AF: 0.837

Gnomad ASJ exome AF: 0.771

Gnomad EAS exome AF: 0.941

Gnomad FIN exome AF: 0.841

Gnomad NFE exome AF: 0.775

Gnomad OTH exome AF: 0.794

GnomAD4 exome AF: 0.788 AC: 1140266 AN: 1446786 Hom.: 451963 Cov.: 27 AF XY: 0.791 AC XY: 568845 AN XY: 719134

African (AFR) AF: 0.936 AC: 30654 AN: 32750

American (AMR) AF: 0.834 AC: 35725 AN: 42820

Ashkenazi Jewish (ASJ) AF: 0.772 AC: 19773 AN: 25622

East Asian (EAS) AF: 0.949 AC: 37545 AN: 39572

South Asian (SAS) AF: 0.915 AC: 76616 AN: 83774

European-Finnish (FIN) AF: 0.837 AC: 44245 AN: 52882

Middle Eastern (MID) AF: 0.789 AC: 4499 AN: 5702

European-Non Finnish (NFE) AF: 0.764 AC: 843119 AN: 1103886

Other (OTH) AF: 0.804 AC: 48090 AN: 59778

GnomAD4 genome AF: 0.838 AC: 127522 AN: 152150 Hom.: 53860 Cov.: 30 AF XY: 0.845 AC XY: 62823 AN XY: 74380

African (AFR) AF: 0.932 AC: 38711 AN: 41522

American (AMR) AF: 0.829 AC: 12681 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.764 AC: 2652 AN: 3472

East Asian (EAS) AF: 0.943 AC: 4887 AN: 5184

South Asian (SAS) AF: 0.918 AC: 4430 AN: 4826

European-Finnish (FIN) AF: 0.832 AC: 8781 AN: 10556

Middle Eastern (MID) AF: 0.776 AC: 228 AN: 294

European-Non Finnish (NFE) AF: 0.776 AC: 52770 AN: 67984

Other (OTH) AF: 0.816 AC: 1720 AN: 2108

Alfa AF: 0.792 Hom.: 27573

Bravo AF: 0.836

Asia WGS AF: 0.930 AC: 3232 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	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	-0.89
CADD	Benign	0.28
DANN	Benign	0.44
PhyloP100		-0.21
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: rs4540437; hg19: chr8-61707725;