chr1-196740644-G-T

Variant names:

• chr1-196740644-G-T
• rs1065489
• NM_000186.4:c.2808G>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.2808G>T​(p.Glu936Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.176 in 1,612,926 control chromosomes in the GnomAD database, including 29,128 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2412 hom., cov: 32)
  • Exomes 𝑓: 0.18 (26716 hom.)
• Consequence: CFH NM_000186.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: -1.31
• Publications: 191 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.9297004E-4).
• BP6: Variant 1-196740644-G-T is Benign according to our data. Variant chr1-196740644-G-T is described in ClinVar as Benign. ClinVar VariationId is 294509.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.464 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFH	NM_000186.4	MANE Select	c.2808G>T	p.Glu936Asp	missense	Exon 18 of 22	NP_000177.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFH	ENST00000367429.9	TSL:1 MANE Select	c.2808G>T	p.Glu936Asp	missense	Exon 18 of 22	ENSP00000356399.4	P08603
	ENSG00000289697	ENST00000696032.1		c.2808G>T	p.Glu936Asp	missense	Exon 18 of 27	ENSP00000512341.1	A0A8Q3SIA1
	CFH	ENST00000466229.5	TSL:1	n.4824G>T		non_coding_transcript_exon	Exon 13 of 16

Frequencies

GnomAD3 genomes AF: 0.154 AC: 23280 AN: 151646 Hom.: 2412 Cov.: 32

Gnomad AFR AF: 0.0598

Gnomad AMI AF: 0.257

Gnomad AMR AF: 0.226

Gnomad ASJ AF: 0.117

Gnomad EAS AF: 0.480

Gnomad SAS AF: 0.150

Gnomad FIN AF: 0.145

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.171

Gnomad OTH AF: 0.160

GnomAD2 exomes AF: 0.205 AC: 51398 AN: 251208 AF XY: 0.196

Gnomad AFR exome AF: 0.0572

Gnomad AMR exome AF: 0.355

Gnomad ASJ exome AF: 0.122

Gnomad EAS exome AF: 0.504

Gnomad FIN exome AF: 0.140

Gnomad NFE exome AF: 0.168

Gnomad OTH exome AF: 0.195

GnomAD4 exome AF: 0.178 AC: 260579 AN: 1461162 Hom.: 26716 Cov.: 34 AF XY: 0.176 AC XY: 128199 AN XY: 726902

African (AFR) AF: 0.0509 AC: 1705 AN: 33470

American (AMR) AF: 0.336 AC: 15018 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.121 AC: 3172 AN: 26120

East Asian (EAS) AF: 0.477 AC: 18909 AN: 39644

South Asian (SAS) AF: 0.142 AC: 12233 AN: 86178

European-Finnish (FIN) AF: 0.141 AC: 7533 AN: 53412

Middle Eastern (MID) AF: 0.148 AC: 852 AN: 5764

European-Non Finnish (NFE) AF: 0.171 AC: 190571 AN: 1111514

Other (OTH) AF: 0.175 AC: 10586 AN: 60364

GnomAD4 genome AF: 0.153 AC: 23273 AN: 151764 Hom.: 2412 Cov.: 32 AF XY: 0.154 AC XY: 11434 AN XY: 74128

African (AFR) AF: 0.0597 AC: 2472 AN: 41402

American (AMR) AF: 0.226 AC: 3447 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.117 AC: 407 AN: 3464

East Asian (EAS) AF: 0.480 AC: 2472 AN: 5150

South Asian (SAS) AF: 0.150 AC: 719 AN: 4794

European-Finnish (FIN) AF: 0.145 AC: 1524 AN: 10484

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.171 AC: 11606 AN: 67914

Other (OTH) AF: 0.158 AC: 332 AN: 2104

Alfa AF: 0.166 Hom.: 7831

Bravo AF: 0.161

TwinsUK AF: 0.165 AC: 612

ALSPAC AF: 0.170 AC: 656

ESP6500AA AF: 0.0663 AC: 292

ESP6500EA AF: 0.175 AC: 1503

ExAC AF: 0.196 AC: 23731

Asia WGS AF: 0.234 AC: 814 AN: 3478

EpiCase AF: 0.172

EpiControl AF: 0.175

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Age related macular degeneration 4 (2)
-	-	2	Basal laminar drusen (2)
-	-	2	Hemolytic uremic syndrome, atypical, susceptibility to, 1 (2)
-	-	2	not specified (2)
-	-	1	CFH-Related Dense Deposit Disease / Membranoproliferative Glomerulonephritis Type II (1)
-	-	1	Factor H deficiency (1)
-	-	1	Factor H deficiency;C0730295:Basal laminar drusen;C1853147:Age related macular degeneration 4;C2749604:Hemolytic uremic syndrome, atypical, susceptibility to, 1 (1)
-	-	1	Factor H deficiency;C0730295:Basal laminar drusen;C1853147:Age related macular degeneration 4;C2931788:Atypical hemolytic-uremic syndrome (1)
-	-	1	Focal segmental glomerulosclerosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.020
DANN	Uncertain	0.99
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.00019	T
MetaSVM	Benign	-0.95	T
PhyloP100		-1.3
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.89	N
REVEL	Benign	0.094
Sift	Benign	0.59	T
Sift4G	Benign	0.48	T
Vest4		0.067
MutPred		0.53		Loss of glycosylation at S938 (P = 0.1269)
MPC		0.20
ClinPred		0.0067	T
GERP RS		-2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.64
Mutation Taster		=84/16	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1065489; hg19: chr1-196709774; COSMIC: COSV66405884;