rs568551629

Positions:

• chr8-60822671-C-A
• chr8-60822671-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP3

The NM_017780.4(CHD7):​c.3126C>A​(p.Asn1042Lys) variant causes a missense change involving the alteration of a non-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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHD7 NM_017780.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.41

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 6 ACMG points.

• PM1: In a domain Helicase ATP-binding (size 174) in uniprot entity CHD7_HUMAN there are 15 pathogenic changes around while only 1 benign (94%) in NM_017780.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CHD7. . Gene score misZ 3.2193 (greater than the threshold 3.09). Trascript score misZ 3.9401 (greater than threshold 3.09). GenCC has associacion of gene with Kallmann syndrome, hypogonadotropic hypogonadism 5 with or without anosmia, CHARGE syndrome, hypogonadotropic hypogonadism, Omenn syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.773

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHD7	NM_017780.4	c.3126C>A	p.Asn1042Lys	missense_variant	12/38	ENST00000423902.7	NP_060250.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHD7	ENST00000423902.7	c.3126C>A	p.Asn1042Lys	missense_variant	12/38	5	NM_017780.4	ENSP00000392028	P1
CHD7	ENST00000524602.5	c.1717-39558C>A		intron_variant		1		ENSP00000437061
CHD7	ENST00000525508.1	c.3126C>A	p.Asn1042Lys	missense_variant	11/12	5		ENSP00000436027
CHD7	ENST00000695853.1	c.3126C>A	p.Asn1042Lys	missense_variant, NMD_transcript_variant	12/37			ENSP00000512218

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

CHARGE syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 17, 2020

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with CHD7-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with lysine at codon 1042 of the CHD7 protein (p.Asn1042Lys). The asparagine residue is highly conserved and there is a moderate physicochemical difference between asparagine and lysine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.043	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	15
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D;.
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.28	N
LIST_S2	Uncertain	0.97	D;D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.77	D;D
MetaSVM	Uncertain	0.31	D
MutationAssessor	Benign	1.0	L;L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.5	D;D
REVEL	Uncertain	0.48
Sift	Uncertain	0.025	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.97	D;B
Vest4		0.78
MutPred		0.75		Gain of MoRF binding (P = 0.0314);Gain of MoRF binding (P = 0.0314);
MVP		0.86
MPC		1.9
ClinPred		0.97	D
GERP RS		-2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.81
gMVP		0.95

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-61735230;