1-196677131-A-G

Variant names:

• chr1-196677131-A-G
• rs572515
• ENST00000466229.5:n.144A>G

Variant summary

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

The ENST00000466229.5(CFH):​n.144A>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.685 in 184,346 control chromosomes in the GnomAD database, including 44,247 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 0.69 (37066 hom., cov: 32)
  • Exomes 𝑓: 0.65 (7181 hom.)
• Consequence: CFH ENST00000466229.5 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0510
• Publications: 26 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=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.926 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000466229.5. 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.428-345A>G		intron	N/A	NP_000177.2
	CFH	NM_001014975.3		c.428-345A>G		intron	N/A	NP_001014975.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFH	ENST00000466229.5	TSL:1	n.144A>G		non_coding_transcript_exon	Exon 1 of 16
	CFH	ENST00000367429.9	TSL:1 MANE Select	c.428-345A>G		intron	N/A	ENSP00000356399.4
	ENSG00000289697	ENST00000696032.1		c.428-345A>G		intron	N/A	ENSP00000512341.1

Frequencies

GnomAD3 genomes AF: 0.692 AC: 104987 AN: 151820 Hom.: 37027 Cov.: 32

Gnomad AFR AF: 0.786

Gnomad AMI AF: 0.517

Gnomad AMR AF: 0.759

Gnomad ASJ AF: 0.690

Gnomad EAS AF: 0.948

Gnomad SAS AF: 0.722

Gnomad FIN AF: 0.562

Gnomad MID AF: 0.674

Gnomad NFE AF: 0.619

Gnomad OTH AF: 0.705

GnomAD4 exome AF: 0.653 AC: 21153 AN: 32408 Hom.: 7181 Cov.: 0 AF XY: 0.653 AC XY: 11269 AN XY: 17248

African (AFR) AF: 0.767 AC: 488 AN: 636

American (AMR) AF: 0.791 AC: 2261 AN: 2858

Ashkenazi Jewish (ASJ) AF: 0.657 AC: 514 AN: 782

East Asian (EAS) AF: 0.934 AC: 1932 AN: 2068

South Asian (SAS) AF: 0.683 AC: 2627 AN: 3844

European-Finnish (FIN) AF: 0.547 AC: 714 AN: 1306

Middle Eastern (MID) AF: 0.571 AC: 64 AN: 112

European-Non Finnish (NFE) AF: 0.600 AC: 11460 AN: 19098

Other (OTH) AF: 0.641 AC: 1093 AN: 1704

GnomAD4 genome AF: 0.692 AC: 105079 AN: 151938 Hom.: 37066 Cov.: 32 AF XY: 0.694 AC XY: 51494 AN XY: 74240

African (AFR) AF: 0.786 AC: 32598 AN: 41478

American (AMR) AF: 0.760 AC: 11574 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.690 AC: 2396 AN: 3472

East Asian (EAS) AF: 0.948 AC: 4901 AN: 5170

South Asian (SAS) AF: 0.722 AC: 3481 AN: 4822

European-Finnish (FIN) AF: 0.562 AC: 5926 AN: 10540

Middle Eastern (MID) AF: 0.667 AC: 196 AN: 294

European-Non Finnish (NFE) AF: 0.619 AC: 42049 AN: 67902

Other (OTH) AF: 0.704 AC: 1489 AN: 2116

Alfa AF: 0.640 Hom.: 85374

Bravo AF: 0.713

Asia WGS AF: 0.794 AC: 2746 AN: 3458

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.6
DANN	Benign	0.30
PhyloP100		0.051
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: rs572515; hg19: chr1-196646261;