1-196689367-G-T

Variant names:

• chr1-196689367-G-T
• rs482934
• NM_000186.4:c.965-53G>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.965-53G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.648 in 1,460,808 control chromosomes in the GnomAD database, including 311,594 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.69 (37084 hom., cov: 33)
  • Exomes 𝑓: 0.64 (274510 hom.)
• Consequence: CFH NM_000186.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.141
• Publications: 13 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=-0.9).
• BP6: Variant 1-196689367-G-T is Benign according to our data. Variant chr1-196689367-G-T is described in ClinVar as Benign. ClinVar VariationId is 1276326.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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000186.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFH	NM_000186.4	MANE Select	c.965-53G>T		intron	N/A	NP_000177.2
	CFH	NM_001014975.3		c.965-53G>T		intron	N/A	NP_001014975.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFH	ENST00000367429.9	TSL:1 MANE Select	c.965-53G>T		intron	N/A	ENSP00000356399.4
	ENSG00000289697	ENST00000696032.1		c.965-53G>T		intron	N/A	ENSP00000512341.1
	CFH	ENST00000630130.2	TSL:1	c.965-53G>T		intron	N/A	ENSP00000487250.1

Frequencies

GnomAD3 genomes AF: 0.692 AC: 105064 AN: 151914 Hom.: 37045 Cov.: 33

Gnomad AFR AF: 0.786

Gnomad AMI AF: 0.520

Gnomad AMR AF: 0.759

Gnomad ASJ AF: 0.690

Gnomad EAS AF: 0.948

Gnomad SAS AF: 0.720

Gnomad FIN AF: 0.564

Gnomad MID AF: 0.674

Gnomad NFE AF: 0.619

Gnomad OTH AF: 0.704

GnomAD4 exome AF: 0.643 AC: 840919 AN: 1308776 Hom.: 274510 AF XY: 0.643 AC XY: 420887 AN XY: 654986

African (AFR) AF: 0.794 AC: 22992 AN: 28968

American (AMR) AF: 0.832 AC: 33946 AN: 40824

Ashkenazi Jewish (ASJ) AF: 0.682 AC: 16892 AN: 24782

East Asian (EAS) AF: 0.940 AC: 33091 AN: 35218

South Asian (SAS) AF: 0.694 AC: 54789 AN: 78916

European-Finnish (FIN) AF: 0.559 AC: 27690 AN: 49532

Middle Eastern (MID) AF: 0.646 AC: 3335 AN: 5162

European-Non Finnish (NFE) AF: 0.618 AC: 612091 AN: 990646

Other (OTH) AF: 0.659 AC: 36093 AN: 54728

GnomAD4 genome AF: 0.692 AC: 105156 AN: 152032 Hom.: 37084 Cov.: 33 AF XY: 0.694 AC XY: 51541 AN XY: 74288

African (AFR) AF: 0.786 AC: 32634 AN: 41534

American (AMR) AF: 0.760 AC: 11587 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.690 AC: 2396 AN: 3470

East Asian (EAS) AF: 0.948 AC: 4889 AN: 5156

South Asian (SAS) AF: 0.721 AC: 3472 AN: 4818

European-Finnish (FIN) AF: 0.564 AC: 5939 AN: 10536

Middle Eastern (MID) AF: 0.667 AC: 196 AN: 294

European-Non Finnish (NFE) AF: 0.619 AC: 42085 AN: 67948

Other (OTH) AF: 0.703 AC: 1486 AN: 2114

Alfa AF: 0.657 Hom.: 4142

Bravo AF: 0.713

Asia WGS AF: 0.793 AC: 2753 AN: 3472

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Factor H deficiency;C0730295:Basal laminar drusen;C1853147:Age related macular degeneration 4;C2931788:Atypical hemolytic-uremic syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.9
DANN	Benign	0.18
PhyloP100		-0.14
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: rs482934; hg19: chr1-196658497; COSMIC: COSV62776949;