1-196706731-A-G

Variant names:

• chr1-196706731-A-G
• rs6695321
• NM_000186.4:c.1337-7004A>G

Variant summary

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

The ENST00000367429.9(CFH):​c.1337-7004A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.37 in 151,888 control chromosomes in the GnomAD database, including 11,912 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 0.37 (11912 hom., cov: 31)
• Consequence: CFH ENST00000367429.9 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.595
• Publications: 22 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 = 0.849 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000367429.9. 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.1337-7004A>G		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.1337-7004A>G		intron	N/A	ENSP00000356399.4
	ENSG00000289697	ENST00000696032.1		c.1337-7004A>G		intron	N/A	ENSP00000512341.1
	CFH	ENST00000466229.5	TSL:1	n.3353-7004A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.370 AC: 56093 AN: 151770 Hom.: 11898 Cov.: 31

Gnomad AFR AF: 0.212

Gnomad AMI AF: 0.393

Gnomad AMR AF: 0.543

Gnomad ASJ AF: 0.369

Gnomad EAS AF: 0.870

Gnomad SAS AF: 0.380

Gnomad FIN AF: 0.412

Gnomad MID AF: 0.320

Gnomad NFE AF: 0.381

Gnomad OTH AF: 0.381

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

GnomAD4 genome AF: 0.370 AC: 56137 AN: 151888 Hom.: 11912 Cov.: 31 AF XY: 0.376 AC XY: 27901 AN XY: 74210

African (AFR) AF: 0.212 AC: 8782 AN: 41428

American (AMR) AF: 0.543 AC: 8295 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.369 AC: 1279 AN: 3470

East Asian (EAS) AF: 0.871 AC: 4475 AN: 5140

South Asian (SAS) AF: 0.380 AC: 1829 AN: 4810

European-Finnish (FIN) AF: 0.412 AC: 4335 AN: 10524

Middle Eastern (MID) AF: 0.320 AC: 94 AN: 294

European-Non Finnish (NFE) AF: 0.381 AC: 25888 AN: 67938

Other (OTH) AF: 0.381 AC: 802 AN: 2106

Alfa AF: 0.380 Hom.: 29157

Bravo AF: 0.381

Asia WGS AF: 0.565 AC: 1961 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	4.6
DANN	Benign	0.66
PhyloP100		0.59
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: rs6695321; hg19: chr1-196675861;