chr1-196689775-G-A

Variant names:

• chr1-196689775-G-A
• rs12029785
• NM_000186.4:c.1159+161G>A

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.1159+161G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.645 in 151,830 control chromosomes in the GnomAD database, including 32,031 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.65 (32031 hom., cov: 32)
• Consequence: CFH NM_000186.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.290
• Publications: 7 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=-0.97).
• BP6: Variant 1-196689775-G-A is Benign according to our data. Variant chr1-196689775-G-A is described in ClinVar as Benign. ClinVar VariationId is 1289573.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.926 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFH	NM_000186.4	c.1159+161G>A		intron_variant	Intron 8 of 21	ENST00000367429.9	NP_000177.2
CFH	NM_001014975.3	c.1159+161G>A		intron_variant	Intron 8 of 9		NP_001014975.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFH	ENST00000367429.9	c.1159+161G>A		intron_variant	Intron 8 of 21	1	NM_000186.4	ENSP00000356399.4
ENSG00000289697	ENST00000696032.1	c.1159+161G>A		intron_variant	Intron 8 of 26			ENSP00000512341.1

Frequencies

GnomAD3 genomes AF: 0.645 AC: 97868 AN: 151712 Hom.: 32007 Cov.: 32

Gnomad AFR AF: 0.629

Gnomad AMI AF: 0.520

Gnomad AMR AF: 0.737

Gnomad ASJ AF: 0.663

Gnomad EAS AF: 0.948

Gnomad SAS AF: 0.720

Gnomad FIN AF: 0.564

Gnomad MID AF: 0.668

Gnomad NFE AF: 0.618

Gnomad OTH AF: 0.665

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.645 AC: 97933 AN: 151830 Hom.: 32031 Cov.: 32 AF XY: 0.648 AC XY: 48091 AN XY: 74194

African (AFR) AF: 0.629 AC: 26059 AN: 41430

American (AMR) AF: 0.738 AC: 11229 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.663 AC: 2298 AN: 3468

East Asian (EAS) AF: 0.949 AC: 4889 AN: 5154

South Asian (SAS) AF: 0.721 AC: 3469 AN: 4814

European-Finnish (FIN) AF: 0.564 AC: 5928 AN: 10514

Middle Eastern (MID) AF: 0.656 AC: 193 AN: 294

European-Non Finnish (NFE) AF: 0.618 AC: 41992 AN: 67910

Other (OTH) AF: 0.664 AC: 1402 AN: 2110

Alfa AF: 0.534 Hom.: 1762

Bravo AF: 0.661

Asia WGS AF: 0.780 AC: 2710 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 10, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.54
DANN	Benign	0.16
PhyloP100		-0.29
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: rs12029785; hg19: chr1-196658905;