1-196692408-A-T

Variant names:

• chr1-196692408-A-T
• rs12124794
• NM_000186.4:c.1336+2169A>T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000186.4(CFH):​c.1336+2169A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.165 in 807,224 control chromosomes in the GnomAD database, including 12,378 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.19 (3446 hom., cov: 32)
  • Exomes 𝑓: 0.16 (8932 hom.)
• Consequence: CFH NM_000186.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.266

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.348 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFH	NM_000186.4	c.1336+2169A>T		intron_variant	Intron 9 of 21	ENST00000367429.9	NP_000177.2
CFH	NM_001014975.3	c.1336+2169A>T		intron_variant	Intron 9 of 9		NP_001014975.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFH	ENST00000367429.9	c.1336+2169A>T		intron_variant	Intron 9 of 21	1	NM_000186.4	ENSP00000356399.4
ENSG00000289697	ENST00000696032.1	c.1336+2169A>T		intron_variant	Intron 9 of 26			ENSP00000512341.1

Frequencies

GnomAD3 genomes AF: 0.194 AC: 29493 AN: 151870 Hom.: 3436 Cov.: 32

Gnomad AFR AF: 0.0785

Gnomad AMI AF: 0.136

Gnomad AMR AF: 0.312

Gnomad ASJ AF: 0.256

Gnomad EAS AF: 0.361

Gnomad SAS AF: 0.230

Gnomad FIN AF: 0.260

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.210

Gnomad OTH AF: 0.209

GnomAD4 exome AF: 0.158 AC: 103312 AN: 655238 Hom.: 8932 Cov.: 8 AF XY: 0.158 AC XY: 48137 AN XY: 304750

Gnomad4 AFR exome AF: 0.0487

Gnomad4 AMR exome AF: 0.277

Gnomad4 ASJ exome AF: 0.185

Gnomad4 EAS exome AF: 0.276

Gnomad4 SAS exome AF: 0.165

Gnomad4 FIN exome AF: 0.212

Gnomad4 NFE exome AF: 0.159

Gnomad4 OTH exome AF: 0.155

GnomAD4 genome AF: 0.194 AC: 29514 AN: 151986 Hom.: 3446 Cov.: 32 AF XY: 0.200 AC XY: 14857 AN XY: 74290

Gnomad4 AFR AF: 0.0783

Gnomad4 AMR AF: 0.313

Gnomad4 ASJ AF: 0.256

Gnomad4 EAS AF: 0.362

Gnomad4 SAS AF: 0.231

Gnomad4 FIN AF: 0.260

Gnomad4 NFE AF: 0.210

Gnomad4 OTH AF: 0.210

Alfa AF: 0.0798 Hom.: 134

Bravo AF: 0.194

Asia WGS AF: 0.307 AC: 1065 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	3.5
DANN	Benign	0.23

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: rs12124794; hg19: chr1-196661538;