1-196677257-T-C

Variant names:

• chr1-196677257-T-C
• rs1329423
• ENST00000466229.5:n.270T>C

Variant summary

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

The ENST00000466229.5(CFH):​n.270T>C 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 0.255 in 474,706 control chromosomes in the GnomAD database, including 17,796 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 0.22 (4507 hom., cov: 32)
  • Exomes 𝑓: 0.27 (13289 hom.)
• Consequence: CFH ENST00000466229.5 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.416
• Publications: 19 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=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.493 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFH	NM_000186.4	c.428-219T>C		intron_variant	Intron 4 of 21	ENST00000367429.9	NP_000177.2
CFH	NM_001014975.3	c.428-219T>C		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.428-219T>C		intron_variant	Intron 4 of 21	1	NM_000186.4	ENSP00000356399.4
ENSG00000289697	ENST00000696032.1	c.428-219T>C		intron_variant	Intron 4 of 26			ENSP00000512341.1

Frequencies

GnomAD3 genomes AF: 0.222 AC: 33655 AN: 151852 Hom.: 4504 Cov.: 32

Gnomad AFR AF: 0.0981

Gnomad AMI AF: 0.266

Gnomad AMR AF: 0.276

Gnomad ASJ AF: 0.287

Gnomad EAS AF: 0.509

Gnomad SAS AF: 0.231

Gnomad FIN AF: 0.181

Gnomad MID AF: 0.357

Gnomad NFE AF: 0.264

Gnomad OTH AF: 0.231

GnomAD4 exome AF: 0.271 AC: 87372 AN: 322736 Hom.: 13289 Cov.: 3 AF XY: 0.269 AC XY: 45564 AN XY: 169352

African (AFR) AF: 0.0960 AC: 962 AN: 10026

American (AMR) AF: 0.336 AC: 4251 AN: 12652

Ashkenazi Jewish (ASJ) AF: 0.278 AC: 2829 AN: 10162

East Asian (EAS) AF: 0.505 AC: 11835 AN: 23416

South Asian (SAS) AF: 0.220 AC: 6618 AN: 30118

European-Finnish (FIN) AF: 0.185 AC: 3561 AN: 19280

Middle Eastern (MID) AF: 0.257 AC: 367 AN: 1430

European-Non Finnish (NFE) AF: 0.264 AC: 51882 AN: 196608

Other (OTH) AF: 0.266 AC: 5067 AN: 19044

GnomAD4 genome AF: 0.221 AC: 33655 AN: 151970 Hom.: 4507 Cov.: 32 AF XY: 0.220 AC XY: 16365 AN XY: 74286

African (AFR) AF: 0.0980 AC: 4066 AN: 41504

American (AMR) AF: 0.276 AC: 4207 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.287 AC: 996 AN: 3468

East Asian (EAS) AF: 0.509 AC: 2618 AN: 5142

South Asian (SAS) AF: 0.232 AC: 1116 AN: 4812

European-Finnish (FIN) AF: 0.181 AC: 1911 AN: 10582

Middle Eastern (MID) AF: 0.360 AC: 105 AN: 292

European-Non Finnish (NFE) AF: 0.264 AC: 17909 AN: 67914

Other (OTH) AF: 0.230 AC: 485 AN: 2108

Alfa AF: 0.255 Hom.: 8841

Bravo AF: 0.229

Asia WGS AF: 0.291 AC: 1012 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	7.8
DANN	Benign	0.80
PhyloP100		0.42
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: rs1329423; hg19: chr1-196646387;