chr1-196692386-G-T

Variant names:

• chr1-196692386-G-T
• rs149387455
• NM_000186.4:c.1336+2147G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000186.4(CFH):​c.1336+2147G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000725 in 838,410 control chromosomes in the GnomAD database, including 6 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 0.0015 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00056 (5 hom.)
• Consequence: CFH NM_000186.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.113

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00146 (222/152020) while in subpopulation AFR AF = 0.00263 (109/41458). AF 95% confidence interval is 0.00223. There are 1 homozygotes in GnomAd4. There are 99 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFH	NM_000186.4	c.1336+2147G>T		intron_variant	Intron 9 of 21	ENST00000367429.9	NP_000177.2
CFH	NM_001014975.3	c.1336+2147G>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+2147G>T		intron_variant	Intron 9 of 21	1	NM_000186.4	ENSP00000356399.4
ENSG00000289697	ENST00000696032.1	c.1336+2147G>T		intron_variant	Intron 9 of 26			ENSP00000512341.1

Frequencies

GnomAD3 genomes AF: 0.00145 AC: 220 AN: 151902 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00261

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000788

Gnomad ASJ AF: 0.0158

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.00191

GnomAD4 exome AF: 0.000562 AC: 386 AN: 686390 Hom.: 5 Cov.: 8 AF XY: 0.000542 AC XY: 173 AN XY: 319196

African (AFR) AF: 0.00564 AC: 75 AN: 13308

American (AMR) AF: 0.00 AC: 0 AN: 716

Ashkenazi Jewish (ASJ) AF: 0.0182 AC: 76 AN: 4168

East Asian (EAS) AF: 0.00 AC: 0 AN: 2606

South Asian (SAS) AF: 0.000151 AC: 2 AN: 13208

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 238

Middle Eastern (MID) AF: 0.00725 AC: 10 AN: 1380

European-Non Finnish (NFE) AF: 0.000280 AC: 176 AN: 628504

Other (OTH) AF: 0.00211 AC: 47 AN: 22262

GnomAD4 genome AF: 0.00146 AC: 222 AN: 152020 Hom.: 1 Cov.: 33 AF XY: 0.00133 AC XY: 99 AN XY: 74324

African (AFR) AF: 0.00263 AC: 109 AN: 41458

American (AMR) AF: 0.000786 AC: 12 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.0158 AC: 55 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10550

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000588 AC: 40 AN: 67980

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

Alfa AF: 0.00153 Hom.: 0

Bravo AF: 0.00156

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	10
DANN	Benign	0.49
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	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

Publications

LitVar

Other links and lift over

dbSNP: rs149387455; hg19: chr1-196661516;