rs121913057

Positions:

• chr1-196737575-T-A
• chr1-196737575-T-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_000186.4(CFH):​c.2697T>A​(p.Tyr899*) variant causes a stop gained 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 Pathogenic,risk factor (no stars). Synonymous variant affecting the same amino acid position (i.e. Y899Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CFH NM_000186.4 stop_gained
• Clinical Significance: Pathogenic; risk factor no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: -0.311

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 Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-196737575-T-A is Pathogenic according to our data. Variant chr1-196737575-T-A is described in ClinVar as [Pathogenic, risk_factor]. Clinvar id is 16553.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFH	NM_000186.4	c.2697T>A	p.Tyr899*	stop_gained	17/22	ENST00000367429.9	NP_000177.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFH	ENST00000367429.9	c.2697T>A	p.Tyr899*	stop_gained	17/22	1	NM_000186.4	ENSP00000356399.4
ENSG00000289697	ENST00000696032.1	c.2697T>A	p.Tyr899*	stop_gained	17/27			ENSP00000512341.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic; risk factor

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Hemolytic uremic syndrome, atypical, susceptibility to, 1 Pathogenic:1 Other:1

Pathogenic, no assertion criteria provided	clinical testing	Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	Apr 26, 2019	- -
risk factor, no assertion criteria provided	literature only	OMIM	Mar 01, 2004	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	34
DANN	Uncertain	0.98
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.043	N
Vest4		0.78
GERP RS		-0.92

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

LitVar

Other links and lift over

dbSNP: rs121913057; hg19: chr1-196706705;