1-196651994-G-T

Variant names:

• chr1-196651994-G-T
• rs527444515
• ENST00000696032.1:c.-124G>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The ENST00000359637.3(CFH):​c.-124G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0011 in 709,794 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00051 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (11 hom.)
• Consequence: CFH ENST00000359637.3 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.859
• Publications: 0 publications found

Genes affected

ENSG00000289697 (HGNC:):

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

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 1-196651994-G-T is Benign according to our data. Variant chr1-196651994-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 294475.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000512 (78/152284) while in subpopulation SAS AF = 0.00725 (35/4828). AF 95% confidence interval is 0.00536. There are 1 homozygotes in GnomAd4. There are 50 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 11 AD,AR,Unknown,SD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000359637.3. 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.-124G>T		upstream_gene	N/A	NP_000177.2
	CFH	NM_001014975.3		c.-124G>T		upstream_gene	N/A	NP_001014975.1	A0A0D9SG88

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000289697	ENST00000696032.1		c.-124G>T		5_prime_UTR	Exon 1 of 27	ENSP00000512341.1	A0A8Q3SIA1
	CFH	ENST00000359637.3	TSL:1	c.-124G>T		5_prime_UTR	Exon 1 of 9	ENSP00000352658.2	Q5TFM2
	CFH	ENST00000695971.1		c.-124G>T		5_prime_UTR	Exon 1 of 22	ENSP00000512298.1	A0A8Q3SIE0

Frequencies

GnomAD3 genomes AF: 0.000513 AC: 78 AN: 152166 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00724

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00191

GnomAD4 exome AF: 0.00126 AC: 702 AN: 557510 Hom.: 11 Cov.: 6 AF XY: 0.00165 AC XY: 495 AN XY: 300722

African (AFR) AF: 0.00 AC: 0 AN: 14956

American (AMR) AF: 0.00101 AC: 30 AN: 29772

Ashkenazi Jewish (ASJ) AF: 0.00437 AC: 81 AN: 18528

East Asian (EAS) AF: 0.00 AC: 0 AN: 32380

South Asian (SAS) AF: 0.00780 AC: 457 AN: 58602

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45362

Middle Eastern (MID) AF: 0.00253 AC: 10 AN: 3948

European-Non Finnish (NFE) AF: 0.000290 AC: 94 AN: 324092

Other (OTH) AF: 0.00100 AC: 30 AN: 29870

GnomAD4 genome AF: 0.000512 AC: 78 AN: 152284 Hom.: 1 Cov.: 32 AF XY: 0.000672 AC XY: 50 AN XY: 74454

African (AFR) AF: 0.0000241 AC: 1 AN: 41576

American (AMR) AF: 0.000523 AC: 8 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00725 AC: 35 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 68018

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.0000530 Hom.: 0

Bravo AF: 0.000416

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Age related macular degeneration 4 (1)
-	-	1	Basal laminar drusen (1)
-	-	1	CFH-Related Dense Deposit Disease / Membranoproliferative Glomerulonephritis Type II (1)
-	-	1	Hemolytic uremic syndrome, atypical, susceptibility to, 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	15
DANN	Benign	0.82
PhyloP100		0.86
PromoterAI		-0.51	Under-expression
Mutation Taster		=297/3	polymorphism

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: rs527444515; hg19: chr1-196621124;