1-196689367-G-T

Variant names:

• chr1-196689367-G-T
• rs482934
• NM_000186.4:c.965-53G>T

Variant summary

Our verdict is Benign. Variant got -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:2
• Conservation: PhyloP100: -0.141

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]

ENSG00000289697 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFH	NM_000186.4	c.965-53G>T		intron_variant	Intron 7 of 21	ENST00000367429.9	NP_000177.2
CFH	NM_001014975.3	c.965-53G>T		intron_variant	Intron 7 of 9		NP_001014975.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFH	ENST00000367429.9	c.965-53G>T		intron_variant	Intron 7 of 21	1	NM_000186.4	ENSP00000356399.4
ENSG00000289697	ENST00000696032.1	c.965-53G>T		intron_variant	Intron 7 of 26			ENSP00000512341.1

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

Gnomad4 AFR exome AF: 0.794

Gnomad4 AMR exome AF: 0.832

Gnomad4 ASJ exome AF: 0.682

Gnomad4 EAS exome AF: 0.940

Gnomad4 SAS exome AF: 0.694

Gnomad4 FIN exome AF: 0.559

Gnomad4 NFE exome AF: 0.618

Gnomad4 OTH exome AF: 0.659

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

Gnomad4 AFR AF: 0.786

Gnomad4 AMR AF: 0.760

Gnomad4 ASJ AF: 0.690

Gnomad4 EAS AF: 0.948

Gnomad4 SAS AF: 0.721

Gnomad4 FIN AF: 0.564

Gnomad4 NFE AF: 0.619

Gnomad4 OTH AF: 0.703

Alfa AF: 0.657 Hom.: 4142

Bravo AF: 0.713

Asia WGS AF: 0.793 AC: 2753 AN: 3472

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	-0.90
CADD	Benign	1.9
DANN	Benign	0.18

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

Publications

LitVar

Other links and lift over

dbSNP: rs482934; hg19: chr1-196658497; COSMIC: COSV62776949;