rs1554597512

chr8-60822103-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP2 PP3_Strong PP5

The NM_017780.4(CHD7):c.2915A>G(p.Gln972Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. Q972Q) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHD7 NM_017780.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 9.32

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, CHD7
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 8-60822103-A-G is Pathogenic according to our data. Variant chr8-60822103-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 488372.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHD7	NM_017780.4	c.2915A>G	p.Gln972Arg	missense_variant	11/38	ENST00000423902.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHD7	ENST00000423902.7	c.2915A>G	p.Gln972Arg	missense_variant	11/38	5	NM_017780.4	P1
CHD7	ENST00000524602.5	c.1717-40126A>G		intron_variant		1
CHD7	ENST00000525508.1	c.2915A>G	p.Gln972Arg	missense_variant	10/12	5
CHD7	ENST00000695853.1	c.2915A>G	p.Gln972Arg	missense_variant, NMD_transcript_variant	11/37

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

CHARGE syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	research	Sbielas Lab-Department of Human Genetics University of Michigan, University of Michigan Medical School	Oct 27, 2017	- -
Likely pathogenic, no assertion criteria provided	research	University of Washington Center for Mendelian Genomics, University of Washington	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.62
Cadd	Pathogenic	30
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	4.7	H;H
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.8	D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;P
Vest4		0.94
MutPred		0.94		Gain of MoRF binding (P = 0.0244);Gain of MoRF binding (P = 0.0244);
MVP		1.0
MPC		1.8
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.99
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1554597512; hg19: chr8-61734662;