rs121434344

Variant names:

• chr8-60816389-C-T
• rs121434344
• NM_017780.4:c.2501C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 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
• Publications: 17 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: Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia, Broad Center for Mendelian Genomics, ClinGen, G2P
• 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 VariationId is 2033.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHD7	ENST00000423902.7	c.2501C>T	p.Ser834Phe	missense_variant, splice_region_variant	Exon 8 of 38	5	NM_017780.4	ENSP00000392028.1
CHD7	ENST00000524602.5	c.1716+35339C>T		intron_variant	Intron 2 of 4	1		ENSP00000437061.1
CHD7	ENST00000525508.1	c.2501C>T	p.Ser834Phe	missense_variant, splice_region_variant	Exon 7 of 12	5		ENSP00000436027.1
CHD7	ENST00000695853.1	n.2501C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 8 of 37			ENSP00000512218.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 22

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000654 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

CHARGE syndrome Pathogenic:1

Oct 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

HYPOGONADOTROPIC HYPOGONADISM 5 WITHOUT ANOSMIA Pathogenic:1

Oct 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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
PhyloP100		7.9
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
Mutation Taster		=3/97	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121434344; hg19: chr8-61728948;