1-196677046-T-G

Variant names:

• chr1-196677046-T-G
• rs1329424
• ENST00000466229.5:n.59T>G

Variant summary

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

The ENST00000466229.5(CFH):​n.59T>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 0.661 in 160,712 control chromosomes in the GnomAD database, including 35,672 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 0.66 (33757 hom., cov: 32)
  • Exomes 𝑓: 0.64 (1915 hom.)
• Consequence: CFH ENST00000466229.5 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.848
• Publications: 44 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=-0.98).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.926 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFH	NM_000186.4	c.428-430T>G		intron_variant	Intron 4 of 21	ENST00000367429.9	NP_000177.2
CFH	NM_001014975.3	c.428-430T>G		intron_variant	Intron 4 of 9		NP_001014975.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFH	ENST00000367429.9	c.428-430T>G		intron_variant	Intron 4 of 21	1	NM_000186.4	ENSP00000356399.4
ENSG00000289697	ENST00000696032.1	c.428-430T>G		intron_variant	Intron 4 of 26			ENSP00000512341.1

Frequencies

GnomAD3 genomes AF: 0.662 AC: 100493 AN: 151794 Hom.: 33731 Cov.: 32

Gnomad AFR AF: 0.688

Gnomad AMI AF: 0.518

Gnomad AMR AF: 0.745

Gnomad ASJ AF: 0.662

Gnomad EAS AF: 0.948

Gnomad SAS AF: 0.722

Gnomad FIN AF: 0.564

Gnomad MID AF: 0.671

Gnomad NFE AF: 0.618

Gnomad OTH AF: 0.678

GnomAD4 exome AF: 0.642 AC: 5649 AN: 8800 Hom.: 1915 Cov.: 0 AF XY: 0.632 AC XY: 2985 AN XY: 4722

African (AFR) AF: 0.500 AC: 14 AN: 28

American (AMR) AF: 0.777 AC: 1103 AN: 1420

Ashkenazi Jewish (ASJ) AF: 0.683 AC: 56 AN: 82

East Asian (EAS) AF: 0.947 AC: 324 AN: 342

South Asian (SAS) AF: 0.667 AC: 728 AN: 1092

European-Finnish (FIN) AF: 0.505 AC: 100 AN: 198

Middle Eastern (MID) AF: 0.625 AC: 5 AN: 8

European-Non Finnish (NFE) AF: 0.588 AC: 3098 AN: 5272

Other (OTH) AF: 0.617 AC: 221 AN: 358

GnomAD4 genome AF: 0.662 AC: 100565 AN: 151912 Hom.: 33757 Cov.: 32 AF XY: 0.665 AC XY: 49372 AN XY: 74220

African (AFR) AF: 0.688 AC: 28550 AN: 41494

American (AMR) AF: 0.746 AC: 11363 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.662 AC: 2295 AN: 3466

East Asian (EAS) AF: 0.948 AC: 4910 AN: 5178

South Asian (SAS) AF: 0.722 AC: 3485 AN: 4824

European-Finnish (FIN) AF: 0.564 AC: 5919 AN: 10504

Middle Eastern (MID) AF: 0.660 AC: 194 AN: 294

European-Non Finnish (NFE) AF: 0.618 AC: 41954 AN: 67898

Other (OTH) AF: 0.677 AC: 1425 AN: 2106

Alfa AF: 0.633 Hom.: 113642

Bravo AF: 0.680

Asia WGS AF: 0.782 AC: 2710 AN: 3466

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.39
DANN	Benign	0.23
PhyloP100		-0.85
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: rs1329424; hg19: chr1-196646176;