chr8-60816389-C-T

Position:

• chr8-60816389-C-T

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.2501C>T​(p.Ser834Phe) variant causes a missense, splice region 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. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHD7 NM_017780.4 missense, splice_region
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 7.90

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 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, 0.98
• PP5: Variant 8-60816389-C-T is Pathogenic according to our data. Variant chr8-60816389-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 2033.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHD7	NM_017780.4	c.2501C>T	p.Ser834Phe	missense_variant, splice_region_variant	8/38	ENST00000423902.7	NP_060250.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHD7	ENST00000423902.7	c.2501C>T	p.Ser834Phe	missense_variant, splice_region_variant	8/38	5	NM_017780.4	ENSP00000392028.1
CHD7	ENST00000524602.5	c.1716+35339C>T		intron_variant		1		ENSP00000437061.1
CHD7	ENST00000525508.1	c.2501C>T	p.Ser834Phe	missense_variant, splice_region_variant	7/12	5		ENSP00000436027.1
CHD7	ENST00000695853.1	n.2501C>T		splice_region_variant, non_coding_transcript_exon_variant	8/37			ENSP00000512218.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 22

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

CHARGE syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2008

- -

Hypogonadotropic hypogonadism 5 without anosmia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2008

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Uncertain	2.9	M;M
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-5.2	D;D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.95
MutPred		0.91		Loss of ubiquitination at K829 (P = 0.1268);Loss of ubiquitination at K829 (P = 0.1268);
MVP		0.99
MPC		0.55
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.97
gMVP		0.83

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: rs121434344; hg19: chr8-61728948;