rs1066420

Variant names:

• chr1-196751925-T-C
• rs1066420
• ENST00000696032.1:c.3580+4728T>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The ENST00000696032.1(ENSG00000289697):​c.3580+4728T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.196 in 146,710 control chromosomes in the GnomAD database, including 227 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 0.20 (227 hom., cov: 30)
• Consequence: ENSG00000289697 ENST00000696032.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.78
• Publications: 4 publications found

Genes affected

ENSG00000289697 (HGNC:):

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

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BS2: High Homozygotes in GnomAd4 at 227 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000289697	ENST00000696032.1	c.3580+4728T>C		intron_variant	Intron 22 of 26			ENSP00000512341.1
CFH	ENST00000695981.1	c.3581-147T>C		intron_variant	Intron 22 of 22			ENSP00000512306.1
ENSG00000289697	ENST00000696033.1	c.1160-27872T>C		intron_variant	Intron 8 of 8			ENSP00000512342.1

Frequencies

GnomAD3 genomes AF: 0.196 AC: 28780 AN: 146600 Hom.: 224 Cov.: 30

Gnomad AFR AF: 0.282

Gnomad AMI AF: 0.211

Gnomad AMR AF: 0.216

Gnomad ASJ AF: 0.126

Gnomad EAS AF: 0.372

Gnomad SAS AF: 0.132

Gnomad FIN AF: 0.121

Gnomad MID AF: 0.172

Gnomad NFE AF: 0.149

Gnomad OTH AF: 0.187

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

GnomAD4 genome AF: 0.196 AC: 28802 AN: 146710 Hom.: 227 Cov.: 30 AF XY: 0.194 AC XY: 13898 AN XY: 71682

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.282 AC: 11096 AN: 39284

American (AMR) AF: 0.215 AC: 3148 AN: 14614

Ashkenazi Jewish (ASJ) AF: 0.126 AC: 429 AN: 3400

East Asian (EAS) AF: 0.371 AC: 1778 AN: 4788

South Asian (SAS) AF: 0.132 AC: 619 AN: 4704

European-Finnish (FIN) AF: 0.121 AC: 1251 AN: 10314

Middle Eastern (MID) AF: 0.172 AC: 50 AN: 290

European-Non Finnish (NFE) AF: 0.149 AC: 9865 AN: 66384

Other (OTH) AF: 0.185 AC: 378 AN: 2042

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.190 Hom.: 20

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.26
DANN	Benign	0.14
PhyloP100		-3.8

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1066420; hg19: chr1-196721055;