rs375046

Variant names:

• chr1-196736796-C-A
• rs375046
• NM_000186.4:c.2414-28C>A

Your query was ambiguous. Multiple possible variants found:

• chr1-196736796-C-A
• chr1-196736796-C-G
• chr1-196736796-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000186.4(CFH):​c.2414-28C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.604 in 1,087,864 control chromosomes in the GnomAD database, including 203,309 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.67 (35104 hom., cov: 32)
  • Exomes 𝑓: 0.59 (168205 hom.)
• Consequence: CFH NM_000186.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.39
• Publications: 12 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 1-196736796-C-A is Benign according to our data. Variant chr1-196736796-C-A is described in ClinVar as Benign. ClinVar VariationId is 1274202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.921 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFH	NM_000186.4	c.2414-28C>A		intron_variant	Intron 15 of 21	ENST00000367429.9	NP_000177.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFH	ENST00000367429.9	c.2414-28C>A		intron_variant	Intron 15 of 21	1	NM_000186.4	ENSP00000356399.4
ENSG00000289697	ENST00000696032.1	c.2414-28C>A		intron_variant	Intron 15 of 26			ENSP00000512341.1

Frequencies

GnomAD3 genomes AF: 0.673 AC: 101133 AN: 150268 Hom.: 35062 Cov.: 32

Gnomad AFR AF: 0.796

Gnomad AMI AF: 0.515

Gnomad AMR AF: 0.747

Gnomad ASJ AF: 0.668

Gnomad EAS AF: 0.943

Gnomad SAS AF: 0.720

Gnomad FIN AF: 0.543

Gnomad MID AF: 0.656

Gnomad NFE AF: 0.578

Gnomad OTH AF: 0.688

GnomAD2 exomes AF: 0.592 AC: 34218 AN: 57840 AF XY: 0.601

Gnomad AFR exome AF: 0.740

Gnomad AMR exome AF: 0.710

Gnomad ASJ exome AF: 0.650

Gnomad EAS exome AF: 0.933

Gnomad FIN exome AF: 0.525

Gnomad NFE exome AF: 0.554

Gnomad OTH exome AF: 0.591

GnomAD4 exome AF: 0.593 AC: 556118 AN: 937488 Hom.: 168205 Cov.: 13 AF XY: 0.593 AC XY: 273463 AN XY: 461044

African (AFR) AF: 0.801 AC: 15272 AN: 19062

American (AMR) AF: 0.757 AC: 7380 AN: 9754

Ashkenazi Jewish (ASJ) AF: 0.648 AC: 10213 AN: 15760

East Asian (EAS) AF: 0.933 AC: 21852 AN: 23432

South Asian (SAS) AF: 0.688 AC: 17762 AN: 25800

European-Finnish (FIN) AF: 0.526 AC: 16904 AN: 32144

Middle Eastern (MID) AF: 0.626 AC: 1721 AN: 2748

European-Non Finnish (NFE) AF: 0.573 AC: 441528 AN: 770832

Other (OTH) AF: 0.619 AC: 23486 AN: 37956

GnomAD4 genome AF: 0.673 AC: 101224 AN: 150376 Hom.: 35104 Cov.: 32 AF XY: 0.677 AC XY: 49744 AN XY: 73428

African (AFR) AF: 0.797 AC: 32917 AN: 41320

American (AMR) AF: 0.748 AC: 11297 AN: 15112

Ashkenazi Jewish (ASJ) AF: 0.668 AC: 2309 AN: 3458

East Asian (EAS) AF: 0.943 AC: 4861 AN: 5156

South Asian (SAS) AF: 0.720 AC: 3471 AN: 4822

European-Finnish (FIN) AF: 0.543 AC: 5314 AN: 9784

Middle Eastern (MID) AF: 0.652 AC: 189 AN: 290

European-Non Finnish (NFE) AF: 0.578 AC: 38960 AN: 67432

Other (OTH) AF: 0.687 AC: 1437 AN: 2092

Alfa AF: 0.622 Hom.: 7954

Bravo AF: 0.695

Asia WGS AF: 0.789 AC: 2680 AN: 3398

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 10, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.091
DANN	Benign	0.12
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs375046; hg19: chr1-196705926;