1-196902462-T-C

Position:

• chr1-196902462-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001201550.3(CFHR4):​c.103T>C​(p.Tyr35His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00107 in 1,611,896 control chromosomes in the GnomAD database, including 80 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0058 (46 hom., cov: 32)
  • Exomes 𝑓: 0.00058 (34 hom.)
• Consequence: CFHR4 NM_001201550.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0100

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]

CFHR4 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 1-196902462-T-C is Benign according to our data. Variant chr1-196902462-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 1336119.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00581 (881/151578) while in subpopulation AFR AF= 0.0207 (850/41146). AF 95% confidence interval is 0.0195. There are 46 homozygotes in gnomad4. There are 440 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 46 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFHR4	NM_001201550.3	c.103T>C	p.Tyr35His	missense_variant	2/10	ENST00000608469.6	NP_001188479.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFHR4	ENST00000608469.6	c.103T>C	p.Tyr35His	missense_variant	2/10	1	NM_001201550.3	ENSP00000477162.2

Frequencies

GnomAD3 genomes AF: 0.00580 AC: 878 AN: 151466 Hom.: 46 Cov.: 32

Gnomad AFR AF: 0.0206

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000736

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.00141 AC: 351 AN: 249534 Hom.: 12 AF XY: 0.000938 AC XY: 127 AN XY: 135346

Gnomad AFR exome AF: 0.0213

Gnomad AMR exome AF: 0.000406

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000354

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000582 AC: 850 AN: 1460318 Hom.: 34 Cov.: 30 AF XY: 0.000484 AC XY: 352 AN XY: 726544

Gnomad4 AFR exome AF: 0.0213

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.00139

GnomAD4 genome AF: 0.00581 AC: 881 AN: 151578 Hom.: 46 Cov.: 32 AF XY: 0.00594 AC XY: 440 AN XY: 74100

Gnomad4 AFR AF: 0.0207

Gnomad4 AMR AF: 0.00132

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000736

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00103 Hom.: 10

Bravo AF: 0.00665

ESP6500AA AF: 0.0228 AC: 86

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00176 AC: 213

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 10, 2020

- -

Kidney disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 01, 2018

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	14
DANN	Benign	0.95
DEOGEN2	Benign	0.048	.;T;.;.
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.55	T;T;T;T
MetaRNN	Benign	0.0040	T;T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.2	.;M;M;.
PROVEAN	Uncertain	-2.4	N;.;D;D
REVEL	Benign	0.15
Sift	Benign	0.10	T;.;D;D
Sift4G	Benign	0.13	T;.;D;D
Polyphen		1.0	.;D;.;.
Vest4		0.25
MVP		0.17
MPC		0.45
ClinPred		0.030	T
GERP RS		-0.67
Varity_R		0.054
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.23		Position offset: -20

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs138792300; hg19: chr1-196871592; COSMIC: COSV99054609;