1-196651811-C-T

Variant names:

• chr1-196651811-C-T
• rs74842824
• ENST00000359637.3:c.-307C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000359637.3(CFH):​c.-307C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00877 in 403,334 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0077 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0094 (25 hom.)
• Consequence: CFH ENST00000359637.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.427
• Publications: 2 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):

• C3 glomerulonephritis

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• atypical hemolytic-uremic syndrome

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• basal laminar drusen

  Inheritance: AD, Unknown Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hemolytic uremic syndrome, atypical, susceptibility to, 1

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• complement factor H deficiency

  Inheritance: AR Classification: STRONG, MODERATE 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 1-196651811-C-T is Benign according to our data. Variant chr1-196651811-C-T is described in ClinVar as Benign. ClinVar VariationId is 2578592.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00772 (1176/152252) while in subpopulation NFE AF = 0.0114 (777/67990). AF 95% confidence interval is 0.0108. There are 11 homozygotes in GnomAd4. There are 533 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 AD,AR,Unknown,SD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000359637.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFH	NM_000186.4	MANE Select	c.-307C>T		upstream_gene	N/A	NP_000177.2
	CFH	NM_001014975.3		c.-307C>T		upstream_gene	N/A	NP_001014975.1	A0A0D9SG88

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFH	ENST00000359637.3	TSL:1	c.-307C>T		5_prime_UTR	Exon 1 of 9	ENSP00000352658.2	Q5TFM2
	CFH	ENST00000695968.1		c.-307C>T		5_prime_UTR	Exon 1 of 8	ENSP00000512295.1	A0A8Q3SI55
	CFH	ENST00000367429.9	TSL:1 MANE Select	c.-307C>T		upstream_gene	N/A	ENSP00000356399.4	P08603

Frequencies

GnomAD3 genomes AF: 0.00772 AC: 1175 AN: 152134 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00246

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0102

Gnomad ASJ AF: 0.0259

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00245

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0114

Gnomad OTH AF: 0.00908

GnomAD4 exome AF: 0.00941 AC: 2362 AN: 251082 Hom.: 25 AF XY: 0.00877 AC XY: 1171 AN XY: 133470

African (AFR) AF: 0.00246 AC: 20 AN: 8134

American (AMR) AF: 0.00853 AC: 88 AN: 10322

Ashkenazi Jewish (ASJ) AF: 0.0339 AC: 260 AN: 7672

East Asian (EAS) AF: 0.00 AC: 0 AN: 15394

South Asian (SAS) AF: 0.00105 AC: 33 AN: 31384

European-Finnish (FIN) AF: 0.00399 AC: 46 AN: 11528

Middle Eastern (MID) AF: 0.0104 AC: 11 AN: 1060

European-Non Finnish (NFE) AF: 0.0117 AC: 1764 AN: 151122

Other (OTH) AF: 0.00968 AC: 140 AN: 14466

GnomAD4 genome AF: 0.00772 AC: 1176 AN: 152252 Hom.: 11 Cov.: 32 AF XY: 0.00716 AC XY: 533 AN XY: 74434

African (AFR) AF: 0.00245 AC: 102 AN: 41556

American (AMR) AF: 0.0102 AC: 156 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0259 AC: 90 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00245 AC: 26 AN: 10596

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0114 AC: 777 AN: 67990

Other (OTH) AF: 0.00899 AC: 19 AN: 2114

Alfa AF: 0.0103 Hom.: 13

Bravo AF: 0.00832

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	4.4
DANN	Benign	0.76
PhyloP100		-0.43
PromoterAI		-0.15	Neutral

Splicing

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

Other links and lift over

dbSNP: rs74842824; hg19: chr1-196620941;