rs1329423

Variant names:

• chr1-196677257-T-A
• rs1329423
• NM_000186.4:c.428-219T>A

Your query was ambiguous. Multiple possible variants found:

• chr1-196677257-T-A
• chr1-196677257-T-C
• chr1-196677257-T-G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000186.4(CFH):​c.428-219T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000309 in 323,378 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000031 (0 hom.)
• Consequence: CFH NM_000186.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.416
• Publications: 19 publications found

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]

CFH Gene-Disease associations (from GenCC):

• primary membranoproliferative glomerulonephritis

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• atypical hemolytic-uremic syndrome

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• hemolytic uremic syndrome, atypical, susceptibility to, 1

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• complement factor H deficiency

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• basal laminar drusen

  Inheritance: Unknown, AD Classification: STRONG, LIMITED 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

ENSG00000289697 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000186.4. 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.428-219T>A		intron	N/A	NP_000177.2
	CFH	NM_001014975.3		c.428-219T>A		intron	N/A	NP_001014975.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFH	ENST00000367429.9	TSL:1 MANE Select	c.428-219T>A		intron	N/A	ENSP00000356399.4
	ENSG00000289697	ENST00000696032.1		c.428-219T>A		intron	N/A	ENSP00000512341.1
	CFH	ENST00000630130.2	TSL:1	c.428-219T>A		intron	N/A	ENSP00000487250.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000309 AC: 1 AN: 323378 Hom.: 0 Cov.: 3 AF XY: 0.00 AC XY: 0 AN XY: 169676

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 10028

American (AMR) AF: 0.00 AC: 0 AN: 12682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10184

East Asian (EAS) AF: 0.0000426 AC: 1 AN: 23482

South Asian (SAS) AF: 0.00 AC: 0 AN: 30146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 19318

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1430

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 197026

Other (OTH) AF: 0.00 AC: 0 AN: 19082

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 8841

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	7.4
DANN	Benign	0.74
PhyloP100		0.42

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: rs1329423; hg19: chr1-196646387;