chr1-196733680-C-T

Variant names:

• chr1-196733680-C-T
• rs1329428
• NM_000186.4:c.2414-3144C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000186.4(CFH):​c.2414-3144C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.44 in 151,724 control chromosomes in the GnomAD database, including 14,822 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.44 (14822 hom., cov: 31)
• Consequence: CFH NM_000186.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.282
• Publications: 132 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BP6: Variant 1-196733680-C-T is Benign according to our data. Variant chr1-196733680-C-T is described in ClinVar as Benign. ClinVar VariationId is 4291475.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.543 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000186.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFH	NM_000186.4	MANE Select	c.2414-3144C>T		intron	N/A	NP_000177.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFH	ENST00000367429.9	TSL:1 MANE Select	c.2414-3144C>T		intron	N/A	ENSP00000356399.4
	ENSG00000289697	ENST00000696032.1		c.2414-3144C>T		intron	N/A	ENSP00000512341.1
	CFH	ENST00000466229.5	TSL:1	n.4430-3144C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.440 AC: 66674 AN: 151606 Hom.: 14806 Cov.: 31

Gnomad AFR AF: 0.463

Gnomad AMI AF: 0.258

Gnomad AMR AF: 0.488

Gnomad ASJ AF: 0.521

Gnomad EAS AF: 0.464

Gnomad SAS AF: 0.561

Gnomad FIN AF: 0.399

Gnomad MID AF: 0.453

Gnomad NFE AF: 0.408

Gnomad OTH AF: 0.470

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

GnomAD4 genome AF: 0.440 AC: 66730 AN: 151724 Hom.: 14822 Cov.: 31 AF XY: 0.446 AC XY: 33073 AN XY: 74134

African (AFR) AF: 0.463 AC: 19137 AN: 41370

American (AMR) AF: 0.488 AC: 7423 AN: 15200

Ashkenazi Jewish (ASJ) AF: 0.521 AC: 1806 AN: 3464

East Asian (EAS) AF: 0.464 AC: 2385 AN: 5138

South Asian (SAS) AF: 0.561 AC: 2699 AN: 4814

European-Finnish (FIN) AF: 0.399 AC: 4207 AN: 10538

Middle Eastern (MID) AF: 0.442 AC: 130 AN: 294

European-Non Finnish (NFE) AF: 0.408 AC: 27712 AN: 67882

Other (OTH) AF: 0.472 AC: 996 AN: 2112

Alfa AF: 0.414 Hom.: 54765

Bravo AF: 0.443

Asia WGS AF: 0.534 AC: 1855 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Factor H deficiency;C0730295:Basal laminar drusen;C1853147:Age related macular degeneration 4;C2931788:Atypical hemolytic-uremic syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	3.6
DANN	Benign	0.36
PhyloP100		0.28
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: rs1329428; hg19: chr1-196702810; COSMIC: COSV66410694; COSMIC: COSV66410694;