rs6677604

Variant names:

• chr1-196717788-G-A
• rs6677604
• NM_000186.4:c.1696+2019G>A

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.1696+2019G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.232 in 151,982 control chromosomes in the GnomAD database, including 4,775 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.23 (4775 hom., cov: 32)
• Consequence: CFH NM_000186.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.529
• Publications: 115 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):

• C3 glomerulonephritis

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

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• basal laminar drusen

  Inheritance: AD, Unknown Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hemolytic uremic syndrome, atypical, susceptibility to, 1

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

  Inheritance: AR Classification: STRONG, MODERATE 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=-0.91).
• BP6: Variant 1-196717788-G-A is Benign according to our data. Variant chr1-196717788-G-A is described in ClinVar as Benign. ClinVar VariationId is 4291412.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.346 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFH	NM_000186.4	MANE Select	c.1696+2019G>A		intron	N/A	NP_000177.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFH	ENST00000367429.9	TSL:1 MANE Select	c.1696+2019G>A		intron	N/A	ENSP00000356399.4	P08603
	ENSG00000289697	ENST00000696032.1		c.1696+2019G>A		intron	N/A	ENSP00000512341.1	A0A8Q3SIA1
	CFH	ENST00000466229.5	TSL:1	n.3712+2019G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.232 AC: 35258 AN: 151864 Hom.: 4777 Cov.: 32

Gnomad AFR AF: 0.351

Gnomad AMI AF: 0.122

Gnomad AMR AF: 0.167

Gnomad ASJ AF: 0.270

Gnomad EAS AF: 0.0548

Gnomad SAS AF: 0.326

Gnomad FIN AF: 0.130

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.196

Gnomad OTH AF: 0.250

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

GnomAD4 genome AF: 0.232 AC: 35267 AN: 151982 Hom.: 4775 Cov.: 32 AF XY: 0.231 AC XY: 17186 AN XY: 74300

African (AFR) AF: 0.351 AC: 14534 AN: 41428

American (AMR) AF: 0.167 AC: 2541 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.270 AC: 939 AN: 3472

East Asian (EAS) AF: 0.0548 AC: 283 AN: 5168

South Asian (SAS) AF: 0.325 AC: 1568 AN: 4824

European-Finnish (FIN) AF: 0.130 AC: 1377 AN: 10588

Middle Eastern (MID) AF: 0.330 AC: 97 AN: 294

European-Non Finnish (NFE) AF: 0.196 AC: 13292 AN: 67958

Other (OTH) AF: 0.250 AC: 525 AN: 2102

Alfa AF: 0.203 Hom.: 16565

Bravo AF: 0.235

Asia WGS AF: 0.198 AC: 688 AN: 3478

ClinVar

ClinVar submissions

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	-0.91
CADD	Benign	0.95
DANN	Benign	0.30
PhyloP100		-0.53
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: rs6677604; hg19: chr1-196686918;