rs41305525

Variant names:

• chr8-60742450-A-G
• rs41305525
• NM_017780.4:c.1018A>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.1018A>G​(p.Met340Val) variant causes a missense change. The variant allele was found at a frequency of 0.00619 in 1,614,006 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 0.0050 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0063 (33 hom.)
• Consequence: CHD7 NM_017780.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: 4.82
• Publications: 20 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 (MetaRNN=0.00827083).
• BP6: Variant 8-60742450-A-G is Benign according to our data. Variant chr8-60742450-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95773.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 = 0.00496 (755/152334) while in subpopulation AMR AF = 0.00915 (140/15300). AF 95% confidence interval is 0.00792. There are 4 homozygotes in GnomAd4. There are 393 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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.1018A>G	p.Met340Val	missense	Exon 2 of 38	NP_060250.2
	CHD7	NM_001316690.1		c.1018A>G	p.Met340Val	missense	Exon 1 of 5	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.1018A>G	p.Met340Val	missense	Exon 2 of 38	ENSP00000392028.1	Q9P2D1-1
	CHD7	ENST00000524602.5	TSL:1	c.1018A>G	p.Met340Val	missense	Exon 1 of 5	ENSP00000437061.1	Q9P2D1-4
	CHD7	ENST00000933299.1		c.1018A>G	p.Met340Val	missense	Exon 2 of 38	ENSP00000603358.1

Frequencies

GnomAD3 genomes AF: 0.00496 AC: 755 AN: 152216 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.00916

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00217

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00707

Gnomad OTH AF: 0.00623

GnomAD2 exomes AF: 0.00462 AC: 1151 AN: 249288 AF XY: 0.00467

Gnomad AFR exome AF: 0.00168

Gnomad AMR exome AF: 0.00359

Gnomad ASJ exome AF: 0.00944

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00167

Gnomad NFE exome AF: 0.00712

Gnomad OTH exome AF: 0.00578

GnomAD4 exome AF: 0.00632 AC: 9236 AN: 1461672 Hom.: 33 Cov.: 32 AF XY: 0.00623 AC XY: 4533 AN XY: 727126

African (AFR) AF: 0.00114 AC: 38 AN: 33480

American (AMR) AF: 0.00373 AC: 167 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00907 AC: 237 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000951 AC: 82 AN: 86256

European-Finnish (FIN) AF: 0.00225 AC: 120 AN: 53402

Middle Eastern (MID) AF: 0.00555 AC: 32 AN: 5768

European-Non Finnish (NFE) AF: 0.00740 AC: 8232 AN: 1111834

Other (OTH) AF: 0.00542 AC: 327 AN: 60372

GnomAD4 genome AF: 0.00496 AC: 755 AN: 152334 Hom.: 4 Cov.: 32 AF XY: 0.00528 AC XY: 393 AN XY: 74494

African (AFR) AF: 0.00108 AC: 45 AN: 41582

American (AMR) AF: 0.00915 AC: 140 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00720 AC: 25 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4822

European-Finnish (FIN) AF: 0.00217 AC: 23 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00707 AC: 481 AN: 68030

Other (OTH) AF: 0.00616 AC: 13 AN: 2110

Alfa AF: 0.00616 Hom.: 3

Bravo AF: 0.00528

TwinsUK AF: 0.00998 AC: 37

ALSPAC AF: 0.00804 AC: 31

ESP6500AA AF: 0.00177 AC: 7

ESP6500EA AF: 0.00745 AC: 62

ExAC AF: 0.00418 AC: 506

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00851

EpiControl AF: 0.00771

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	11	not specified (11)
-	-	5	not provided (5)
-	-	2	CHARGE syndrome (2)
-	-	1	Hypogonadotropic hypogonadism 5 with or without anosmia (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	0.010
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.18
Eigen_PC	Benign	0.017
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.0083	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	0.81	L
PhyloP100		4.8
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.42	N
REVEL	Uncertain	0.32
Sift	Benign	0.080	T
Sift4G	Benign	0.55	T
Polyphen		0.0	B
Vest4		0.60
MVP		0.98
MPC		0.10
ClinPred		0.010	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.44
Mutation Taster		=96/4	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: rs41305525; hg19: chr8-61655009;