rs3753396

Positions:

• chr1-196726612-A-C
• chr1-196726612-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000186.4(CFH):​c.2016A>C​(p.Gln672His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q672Q) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CFH NM_000186.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0700

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFH	NM_000186.4	c.2016A>C	p.Gln672His	missense_variant	13/22	ENST00000367429.9	NP_000177.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFH	ENST00000367429.9	c.2016A>C	p.Gln672His	missense_variant	13/22	1	NM_000186.4	ENSP00000356399	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	15
DANN	Uncertain	1.0
Eigen	Benign	-0.026
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.64	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.048	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Benign	-0.62	T
MutationTaster	Benign	0.96	N
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0050	D
Vest4		0.36
MutPred		0.65		Loss of ubiquitination at K670 (P = 0.0715);
MVP		0.51
MPC		0.48
ClinPred		0.98	D
GERP RS		-2.2
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs3753396; hg19: chr1-196695742;