rs375046

Positions:

• chr1-196736796-C-A
• chr1-196736796-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000186.4(CFH):​c.2414-28C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.604 in 1,087,864 control chromosomes in the GnomAD database, including 203,309 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.67 (35104 hom., cov: 32)
  • Exomes 𝑓: 0.59 (168205 hom.)
• Consequence: CFH NM_000186.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.39

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 1-196736796-C-A is Benign according to our data. Variant chr1-196736796-C-A is described in ClinVar as [Benign]. Clinvar id is 1274202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.921 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFH	NM_000186.4	c.2414-28C>A		intron_variant		ENST00000367429.9	NP_000177.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFH	ENST00000367429.9	c.2414-28C>A		intron_variant		1	NM_000186.4	ENSP00000356399.4
ENSG00000289697	ENST00000696032.1	c.2414-28C>A		intron_variant				ENSP00000512341.1

Frequencies

GnomAD3 genomes AF: 0.673 AC: 101133 AN: 150268 Hom.: 35062 Cov.: 32

Gnomad AFR AF: 0.796

Gnomad AMI AF: 0.515

Gnomad AMR AF: 0.747

Gnomad ASJ AF: 0.668

Gnomad EAS AF: 0.943

Gnomad SAS AF: 0.720

Gnomad FIN AF: 0.543

Gnomad MID AF: 0.656

Gnomad NFE AF: 0.578

Gnomad OTH AF: 0.688

GnomAD3 exomes AF: 0.592 AC: 34218 AN: 57840 Hom.: 10476 AF XY: 0.601 AC XY: 20405 AN XY: 33928

Gnomad AFR exome AF: 0.740

Gnomad AMR exome AF: 0.710

Gnomad ASJ exome AF: 0.650

Gnomad EAS exome AF: 0.933

Gnomad SAS exome AF: 0.685

Gnomad FIN exome AF: 0.525

Gnomad NFE exome AF: 0.554

Gnomad OTH exome AF: 0.591

GnomAD4 exome AF: 0.593 AC: 556118 AN: 937488 Hom.: 168205 Cov.: 13 AF XY: 0.593 AC XY: 273463 AN XY: 461044

Gnomad4 AFR exome AF: 0.801

Gnomad4 AMR exome AF: 0.757

Gnomad4 ASJ exome AF: 0.648

Gnomad4 EAS exome AF: 0.933

Gnomad4 SAS exome AF: 0.688

Gnomad4 FIN exome AF: 0.526

Gnomad4 NFE exome AF: 0.573

Gnomad4 OTH exome AF: 0.619

GnomAD4 genome AF: 0.673 AC: 101224 AN: 150376 Hom.: 35104 Cov.: 32 AF XY: 0.677 AC XY: 49744 AN XY: 73428

Gnomad4 AFR AF: 0.797

Gnomad4 AMR AF: 0.748

Gnomad4 ASJ AF: 0.668

Gnomad4 EAS AF: 0.943

Gnomad4 SAS AF: 0.720

Gnomad4 FIN AF: 0.543

Gnomad4 NFE AF: 0.578

Gnomad4 OTH AF: 0.687

Alfa AF: 0.626 Hom.: 3868

Bravo AF: 0.695

Asia WGS AF: 0.789 AC: 2680 AN: 3398

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 10, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.091
DANN	Benign	0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs375046; hg19: chr1-196705926;