rs381974

Variant names:

• chr1-196723542-A-G
• rs381974
• NM_000186.4:c.1697-1579A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000186.4(CFH):​c.1697-1579A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.655 in 151,972 control chromosomes in the GnomAD database, including 33,397 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.66 (33397 hom., cov: 31)
• Consequence: CFH NM_000186.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.792
• Publications: 15 publications found

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]

CFH Gene-Disease associations (from GenCC):

• primary membranoproliferative glomerulonephritis

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• atypical hemolytic-uremic syndrome

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• hemolytic uremic syndrome, atypical, susceptibility to, 1

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• complement factor H deficiency

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• basal laminar drusen

  Inheritance: Unknown, AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• Doyne honeycomb retinal dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dense deposit disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000289697 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• 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 rank	MANE	Protein	UniProt
CFH	NM_000186.4	c.1697-1579A>G		intron_variant	Intron 11 of 21	ENST00000367429.9	NP_000177.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFH	ENST00000367429.9	c.1697-1579A>G		intron_variant	Intron 11 of 21	1	NM_000186.4	ENSP00000356399.4
ENSG00000289697	ENST00000696032.1	c.1697-1579A>G		intron_variant	Intron 11 of 26			ENSP00000512341.1

Frequencies

GnomAD3 genomes AF: 0.655 AC: 99478 AN: 151854 Hom.: 33359 Cov.: 31

Gnomad AFR AF: 0.735

Gnomad AMI AF: 0.515

Gnomad AMR AF: 0.741

Gnomad ASJ AF: 0.668

Gnomad EAS AF: 0.948

Gnomad SAS AF: 0.713

Gnomad FIN AF: 0.543

Gnomad MID AF: 0.661

Gnomad NFE AF: 0.579

Gnomad OTH AF: 0.675

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

GnomAD4 genome AF: 0.655 AC: 99568 AN: 151972 Hom.: 33397 Cov.: 31 AF XY: 0.660 AC XY: 49006 AN XY: 74266

African (AFR) AF: 0.736 AC: 30485 AN: 41448

American (AMR) AF: 0.741 AC: 11309 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.668 AC: 2317 AN: 3468

East Asian (EAS) AF: 0.948 AC: 4858 AN: 5124

South Asian (SAS) AF: 0.713 AC: 3433 AN: 4818

European-Finnish (FIN) AF: 0.543 AC: 5753 AN: 10586

Middle Eastern (MID) AF: 0.656 AC: 193 AN: 294

European-Non Finnish (NFE) AF: 0.579 AC: 39328 AN: 67958

Other (OTH) AF: 0.674 AC: 1423 AN: 2112

Alfa AF: 0.638 Hom.: 4976

Bravo AF: 0.676

Asia WGS AF: 0.788 AC: 2739 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.9
DANN	Benign	0.35
PhyloP100		-0.79
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs381974; hg19: chr1-196692672;