rs796052138

Variant names:

• chr1-196679670-CAGA-C
• rs796052138
• NM_000186.4:c.671_673delAGA

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4_Supporting PP5

The NM_000186.4(CFH):​c.671_673delAGA​(p.Lys224del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. K224K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CFH NM_000186.4 disruptive_inframe_deletion
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.56

Genes affected

CFH (HGNC:4883): (complement factor H) This gene is a member of the Regulator of Complement Activation (RCA) gene cluster and encodes a protein with twenty short consensus repeat (SCR) domains. This protein is secreted into the bloodstream and has an essential role in the regulation of complement activation, restricting this innate defense mechanism to microbial infections. Mutations in this gene have been associated with hemolytic-uremic syndrome (HUS) and chronic hypocomplementemic nephropathy. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Oct 2011]

ENSG00000289697 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000186.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 1-196679670-CAGA-C is Pathogenic according to our data. Variant chr1-196679670-CAGA-C is described in ClinVar as [Pathogenic]. Clinvar id is 16555.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFH	NM_000186.4	c.671_673delAGA	p.Lys224del	disruptive_inframe_deletion	Exon 6 of 22	ENST00000367429.9	NP_000177.2
CFH	NM_001014975.3	c.671_673delAGA	p.Lys224del	disruptive_inframe_deletion	Exon 6 of 10		NP_001014975.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFH	ENST00000367429.9	c.671_673delAGA	p.Lys224del	disruptive_inframe_deletion	Exon 6 of 22	1	NM_000186.4	ENSP00000356399.4
ENSG00000289697	ENST00000696032.1	c.671_673delAGA	p.Lys224del	disruptive_inframe_deletion	Exon 6 of 27			ENSP00000512341.1

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Factor H deficiency Pathogenic:1

Jul 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.47		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.36		Position offset: 6
DS_AL_spliceai		0.47		Position offset: -47

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

Publications

LitVar

Other links and lift over

dbSNP: rs796052138; hg19: chr1-196648800;