rs3753394

Variant names:

• chr1-196651787-C-T
• rs3753394
• ENST00000359637.3:c.-331C>T

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -16 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_StrongBP6_Strong

The ENST00000359637.3(CFH):c.-331C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. Note: ENST00000359637.3 is not a MANE Select or MANE Plus Clinical transcript for CFH; the reported annotation may differ from that of the MANE-designated reference transcript for this gene. The variant allele was found at a cumulative frequency of 0.257 (AC=84,106) in the gnomAD database across 327,434 control chromosomes, including 12,896 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.511. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Variant has been reported in ClinVar as Benign/Likely Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (5012 hom., cov: 32)
  • Exomes 𝑓: 0.28 (7884 hom.)
• Consequence: CFH ENST00000359637.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.312
• Publications: 117 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:):

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -16 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); No splicing predictor data available.; Germline computational verdict: benign (Strong).
	BP6Reputable source reports benign		ClinVar 2-star benign — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 2 star(s).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.5110 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFH	ENST00000359637.3	TSL:1	c.-331C>T		5_prime_UTR	Exon 1 of 9	ENSP00000352658.2	Q5TFM2
	ENSG00000289697	ENST00000696032.1		c.-331C>T		upstream_gene	N/A	ENSP00000512341.1	A0A8Q3SIA1
	CFH	ENST00000696027.1		c.-331C>T		upstream_gene	N/A	ENSP00000512336.1	A0A8Q3SI99

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 5 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.228	AC:34633	Hom:5008	AN:151936	Cov:32
GnomAD4 exome	AF: 0.282	AC:49479	Hom:7884	AN:175378	Cov:
GnomAD4 genome	AF: 0.228	AC:34627	Hom:5012	AN:152056	Cov:32
TOPMed (Bravo)	AF: 0.232	AC:61526	Hom:9065	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.274	AC:149303	Hom:21967	AN:544442	Cov:
Local & regional cohorts 10 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.260	AC:608	Hom:89	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.531	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.273	AC:82	Hom:	AN:300	Cov:
GenomeAsia100K	AF: 0.308	AC:1073	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.502	AC:3630	Hom:	AN:7232	Cov:
Qatari Genome	AF: 0.398	AC:70	Hom:	AN:176	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.518	AC:63469	Hom:16431	AN:122544	Cov:
Turkish Variome	AF: 0.303	AC:469	Hom:70	AN:1546	Cov:
UK10K	AF: 0.286	AC:2165	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.562	AC:5035	Hom:1435	AN:8960	Cov:

Showing 15 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.127	2918	22944	0.138	6543	47580

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	CFH-related disorder (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	5.4
BayesDel_noAF	Benign	-0.80
CADD	Benign	3.1
DANN	Benign	0.76
GPN-Star LLR	N/A	0.57
GPN-Star score	N/A	-0.57
Mutation Taster	N/A	100/0	polymorphism
PhyloP100	Benign	-0.31
PromoterAI	N/A	0.0025	Neutral

Showing 9 of 9 scores

Splicing Scores

No splicing scores have been computed for this variant.

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs3753394;

hg19: chr1-196620917;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar