1-196905226-G-T

Position:

• chr1-196905226-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001201550.3(CFHR4):​c.375G>T​(p.Glu125Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.993 in 151,414 control chromosomes in the GnomAD database, including 74,762 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.99 (74762 hom., cov: 32)
  • Exomes 𝑓: 1.0 (728987 hom.)
  • Failed GnomAD Quality Control
• Consequence: CFHR4 NM_001201550.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.00500

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.0240383E-6).
• BP6: Variant 1-196905226-G-T is Benign according to our data. Variant chr1-196905226-G-T is described in ClinVar as [Benign]. Clinvar id is 1232884.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-196905226-G-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFHR4	NM_001201550.3	c.375G>T	p.Glu125Asp	missense_variant	3/10	ENST00000608469.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFHR4	ENST00000608469.6	c.375G>T	p.Glu125Asp	missense_variant	3/10	1	NM_001201550.3	P4

Frequencies

GnomAD3 genomes AF: 0.993 AC: 150314 AN: 151300 Hom.: 74706 Cov.: 32

Gnomad AFR AF: 0.978

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.997

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.996

GnomAD3 exomes AF: 0.998 AC: 247056 AN: 247460 Hom.: 123340 AF XY: 0.999 AC XY: 133900 AN XY: 134064

Gnomad AFR exome AF: 0.978

Gnomad AMR exome AF: 0.999

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.999

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.999 AC: 1458871 AN: 1459860 Hom.: 728987 Cov.: 65 AF XY: 0.999 AC XY: 725752 AN XY: 726204

Gnomad4 AFR exome AF: 0.977

Gnomad4 AMR exome AF: 0.999

Gnomad4 ASJ exome AF: 1.00

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 1.00

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 1.00

Gnomad4 OTH exome AF: 0.998

GnomAD4 genome AF: 0.993 AC: 150427 AN: 151414 Hom.: 74762 Cov.: 32 AF XY: 0.994 AC XY: 73508 AN XY: 73960

Gnomad4 AFR AF: 0.978

Gnomad4 AMR AF: 0.997

Gnomad4 ASJ AF: 1.00

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 1.00

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 1.00

Gnomad4 OTH AF: 0.996

Alfa AF: 0.997 Hom.: 13861

Bravo AF: 0.993

TwinsUK AF: 1.00 AC: 3708

ALSPAC AF: 1.00 AC: 3853

ExAC AF: 0.998 AC: 121118

Asia WGS AF: 0.998 AC: 3464 AN: 3470

EpiCase AF: 1.00

EpiControl AF: 1.00

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.24
DANN	Benign	0.56
DEOGEN2	Benign	0.012	.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.00063	N
LIST_S2	Benign	0.21	T;T
MetaRNN	Benign	0.0000010	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.8	.;N
MutationTaster	Benign	1.0	P;P;P;P
PROVEAN	Benign	0.78	N;.
REVEL	Benign	0.042
Sift	Benign	1.0	T;.
Sift4G	Benign	1.0	T;.
Vest4		0.0090
MutPred		0.45		Loss of disorder (P = 0.1677);.;
MPC		0.061
ClinPred		0.0019	T
GERP RS		2.3
Varity_R		0.034
gMVP		0.30

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: rs10801578; hg19: chr1-196874356;