1-196652039-A-G

Position:

• chr1-196652039-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000359637(CFH):​c.-79A>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0056 in 1,003,852 control chromosomes in the GnomAD database, including 184 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (111 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (73 hom.)
• Consequence: CFH ENST00000359637 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.66

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 1-196652039-A-G is Benign according to our data. Variant chr1-196652039-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 294476.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0737 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFH	NM_000186.4	c.-79A>G		upstream_gene_variant		ENST00000367429.9	NP_000177.2
CFH	NM_001014975.3	c.-79A>G		upstream_gene_variant			NP_001014975.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENSG00000289697	ENST00000696032	c.-79A>G		5_prime_UTR_premature_start_codon_gain_variant	1/27			ENSP00000512341.1
ENSG00000289697	ENST00000696032	c.-79A>G		5_prime_UTR_variant	1/27			ENSP00000512341.1
CFH	ENST00000367429.9	c.-79A>G		upstream_gene_variant		1	NM_000186.4	ENSP00000356399.4

Frequencies

GnomAD3 genomes AF: 0.0219 AC: 3335 AN: 152144 Hom.: 112 Cov.: 32

Gnomad AFR AF: 0.0760

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00897

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.0168

GnomAD4 exome AF: 0.00268 AC: 2281 AN: 851590 Hom.: 73 Cov.: 12 AF XY: 0.00220 AC XY: 986 AN XY: 448178

Gnomad4 AFR exome AF: 0.0789

Gnomad4 AMR exome AF: 0.00409

Gnomad4 ASJ exome AF: 0.0000453

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000314

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000179

Gnomad4 OTH exome AF: 0.00616

GnomAD4 genome AF: 0.0219 AC: 3340 AN: 152262 Hom.: 111 Cov.: 32 AF XY: 0.0213 AC XY: 1583 AN XY: 74460

Gnomad4 AFR AF: 0.0759

Gnomad4 AMR AF: 0.00896

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.0166

Alfa AF: 0.00391 Hom.: 28

Bravo AF: 0.0256

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

CFH-Related Dense Deposit Disease / Membranoproliferative Glomerulonephritis Type II Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Hemolytic uremic syndrome, atypical, susceptibility to, 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Age related macular degeneration 4 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Basal laminar drusen Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.31
DANN	Benign	0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs35906110; hg19: chr1-196621169;