NM_001201550.3:c.119G>A

Variant names:

• chr1-196902478-G-A
• rs200977143
• NM_001201550.3:c.119G>A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001201550.3(CFHR4):​c.119G>A​(p.Arg40His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000584 in 1,611,832 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R40C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00042 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00060 (11 hom.)
• Consequence: CFHR4 NM_001201550.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: -0.337

Genes affected

CFHR4 (HGNC:16979): (complement factor H related 4) This gene is a member of the complement factor H (CFH) gene family, and encodes one of the 5 CFH-related (CFHR) proteins. These 5 genes are closely linked to the CFH gene on chromosome 1q31-q32. The CFHRs are secreted plasma proteins synthesized primarily by the hepatocytes, and composed of highly-related short consensus repeats (SCRs). This protein enhances the cofactor activity of CFH, and is involved in complement regulation. It can associate with lipoproteins and may play a role in lipid metabolism. Alternatively spliced transcript variants encoding different isoforms (varying in the number of SCRs) have been described for this gene. [provided by RefSeq, Jan 2011]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05288759).
• BS2: High Homozygotes in GnomAdExome4 at 11 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFHR4	NM_001201550.3	c.119G>A	p.Arg40His	missense_variant	Exon 2 of 10	ENST00000608469.6	NP_001188479.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFHR4	ENST00000608469.6	c.119G>A	p.Arg40His	missense_variant	Exon 2 of 10	1	NM_001201550.3	ENSP00000477162.2

Frequencies

GnomAD3 genomes AF: 0.000423 AC: 64 AN: 151340 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000585

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000659

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000477

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000471

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000280 AC: 70 AN: 249706 Hom.: 0 AF XY: 0.000317 AC XY: 43 AN XY: 135460

Gnomad AFR exome AF: 0.000516

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.000232

Gnomad NFE exome AF: 0.000380

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000601 AC: 878 AN: 1460380 Hom.: 11 Cov.: 30 AF XY: 0.000619 AC XY: 450 AN XY: 726598

Gnomad4 AFR exome AF: 0.000360

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000267

Gnomad4 FIN exome AF: 0.000244

Gnomad4 NFE exome AF: 0.000724

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.000423 AC: 64 AN: 151452 Hom.: 0 Cov.: 32 AF XY: 0.000378 AC XY: 28 AN XY: 74020

Gnomad4 AFR AF: 0.000584

Gnomad4 AMR AF: 0.0000658

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.000477

Gnomad4 NFE AF: 0.000471

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000286 Hom.: 0

Bravo AF: 0.000412

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000254 AC: 1

ESP6500EA AF: 0.000713 AC: 6

ExAC AF: 0.000223 AC: 27

EpiCase AF: 0.000273

EpiControl AF: 0.000474

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:4

Aug 22, 2024

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A CFHR4 c.119G>A (p.Arg40His) variant was identified. This variant, to our knowledge, has not been reported in the medical literature. This variant is observed on 84/280,886 alleles in the general population (gnomAD v2.1.1). This variant has been reported in the ClinVar database as a germline variant of uncertain significance by two submitters (ClinVar Variation ID: 827994). Computational predictors suggest that the variant does not impact CFHR4 function. Due to limited information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of the CFHR4 c.119G>A (p.Arg40His) variant is uncertain at this time. -

Mar 30, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CFHR4 NM_001201550.2 exon2 p.Arg40His (c.119G>A): This variant has not been reported in the literature but is present in 0.04% (12/24092) of African alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/1-196871608-G-A). Evolutionary conservation tools for this variant are limited or unavailable. Computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sep 05, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BP4 -

not specified Uncertain:1

Aug 13, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.119G>A (p.R40H) alteration is located in exon 2 (coding exon 2) of the CFHR4 gene. This alteration results from a G to A substitution at nucleotide position 119, causing the arginine (R) at amino acid position 40 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	5.4
DANN	Benign	0.87
DEOGEN2	Benign	0.047	.;T;.;.
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.0023	N
LIST_S2	Benign	0.56	T;T;T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.053	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.1	.;M;M;.
PROVEAN	Benign	0.18	N;.;N;N
REVEL	Benign	0.094
Sift	Benign	0.34	T;.;T;T
Sift4G	Benign	0.35	T;.;T;T
Polyphen		1.0	.;D;.;.
Vest4		0.045
MVP		0.36
MPC		0.44
ClinPred		0.049	T
GERP RS		-3.9
Varity_R		0.022
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs200977143; hg19: chr1-196871608; COSMIC: COSV52231181;