rs203674

Positions:

• chr1-196715495-G-T

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.1520-98G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.628 in 934,154 control chromosomes in the GnomAD database, including 188,747 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (33427 hom., cov: 33)
  • Exomes 𝑓: 0.62 (155320 hom.)
• Consequence: CFH NM_000186.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.946

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BP6: Variant 1-196715495-G-T is Benign according to our data. Variant chr1-196715495-G-T is described in ClinVar as [Benign]. Clinvar id is 1258057.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.926 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFH	NM_000186.4	c.1520-98G>T		intron_variant		ENST00000367429.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFH	ENST00000367429.9	c.1520-98G>T		intron_variant		1	NM_000186.4	P2

Frequencies

GnomAD3 genomes AF: 0.655 AC: 99559 AN: 151886 Hom.: 33388 Cov.: 33

Gnomad AFR AF: 0.736

Gnomad AMI AF: 0.514

Gnomad AMR AF: 0.741

Gnomad ASJ AF: 0.668

Gnomad EAS AF: 0.947

Gnomad SAS AF: 0.712

Gnomad FIN AF: 0.545

Gnomad MID AF: 0.662

Gnomad NFE AF: 0.579

Gnomad OTH AF: 0.675

GnomAD4 exome AF: 0.623 AC: 487239 AN: 782150 Hom.: 155320 AF XY: 0.624 AC XY: 258014 AN XY: 413726

Gnomad4 AFR exome AF: 0.736

Gnomad4 AMR exome AF: 0.816

Gnomad4 ASJ exome AF: 0.659

Gnomad4 EAS exome AF: 0.939

Gnomad4 SAS exome AF: 0.687

Gnomad4 FIN exome AF: 0.539

Gnomad4 NFE exome AF: 0.578

Gnomad4 OTH exome AF: 0.628

GnomAD4 genome AF: 0.656 AC: 99650 AN: 152004 Hom.: 33427 Cov.: 33 AF XY: 0.660 AC XY: 49022 AN XY: 74248

Gnomad4 AFR AF: 0.736

Gnomad4 AMR AF: 0.741

Gnomad4 ASJ AF: 0.668

Gnomad4 EAS AF: 0.948

Gnomad4 SAS AF: 0.712

Gnomad4 FIN AF: 0.545

Gnomad4 NFE AF: 0.579

Gnomad4 OTH AF: 0.674

Alfa AF: 0.605 Hom.: 10340

Bravo AF: 0.676

Asia WGS AF: 0.787 AC: 2728 AN: 3472

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.49
DANN	Benign	0.47

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: rs203674; hg19: chr1-196684625;