rs203674

Variant names:

• chr1-196715495-G-T
• rs203674
• NM_000186.4:c.1520-98G>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 20 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 -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 VariationId 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 rank	MANE	Protein	UniProt
CFH	NM_000186.4	c.1520-98G>T		intron_variant	Intron 10 of 21	ENST00000367429.9	NP_000177.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFH	ENST00000367429.9	c.1520-98G>T		intron_variant	Intron 10 of 21	1	NM_000186.4	ENSP00000356399.4
ENSG00000289697	ENST00000696032.1	c.1520-98G>T		intron_variant	Intron 10 of 26			ENSP00000512341.1

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

African (AFR) AF: 0.736 AC: 14654 AN: 19916

American (AMR) AF: 0.816 AC: 32850 AN: 40266

Ashkenazi Jewish (ASJ) AF: 0.659 AC: 13916 AN: 21102

East Asian (EAS) AF: 0.939 AC: 33034 AN: 35178

South Asian (SAS) AF: 0.687 AC: 47898 AN: 69708

European-Finnish (FIN) AF: 0.539 AC: 23497 AN: 43626

Middle Eastern (MID) AF: 0.632 AC: 2527 AN: 3996

European-Non Finnish (NFE) AF: 0.578 AC: 295188 AN: 510646

Other (OTH) AF: 0.628 AC: 23675 AN: 37712

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

African (AFR) AF: 0.736 AC: 30532 AN: 41500

American (AMR) AF: 0.741 AC: 11293 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.668 AC: 2319 AN: 3472

East Asian (EAS) AF: 0.948 AC: 4911 AN: 5182

South Asian (SAS) AF: 0.712 AC: 3436 AN: 4828

European-Finnish (FIN) AF: 0.545 AC: 5746 AN: 10546

Middle Eastern (MID) AF: 0.658 AC: 192 AN: 292

European-Non Finnish (NFE) AF: 0.579 AC: 39327 AN: 67924

Other (OTH) AF: 0.674 AC: 1425 AN: 2114

Alfa AF: 0.613 Hom.: 12882

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

May 10, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.49
DANN	Benign	0.47
PhyloP100		-0.95
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs203674; hg19: chr1-196684625;