rs370026617

Variant names:

• chr1-196888191-C-A
• rs370026617
• NM_001201550.3:c.41C>A

Your query was ambiguous. Multiple possible variants found:

• chr1-196888191-C-A
• chr1-196888191-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001201550.3(CFHR4):​c.41C>A​(p.Ser14Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000559 in 1,611,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: CFHR4 NM_001201550.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.05
• Publications: 1 publications found

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

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.15960523).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001201550.3. 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
	CFHR4	NM_001201550.3	MANE Select	c.41C>A	p.Ser14Tyr	missense	Exon 1 of 10	NP_001188479.1	Q92496-1
	CFHR4	NM_001201551.2		c.41C>A	p.Ser14Tyr	missense	Exon 1 of 10	NP_001188480.1	Q92496-2
	CFHR4	NM_006684.5		c.41C>A	p.Ser14Tyr	missense	Exon 1 of 6	NP_006675.2	Q92496-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFHR4	ENST00000608469.6	TSL:1 MANE Select	c.41C>A	p.Ser14Tyr	missense	Exon 1 of 10	ENSP00000477162.2	Q92496-1
	CFHR4	ENST00000251424.8	TSL:1	c.41C>A	p.Ser14Tyr	missense	Exon 1 of 6	ENSP00000251424.4	Q92496-3
	CFHR4	ENST00000367416.6	TSL:2	c.41C>A	p.Ser14Tyr	missense	Exon 1 of 10	ENSP00000356386.2	Q92496-2

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000295

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251104 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000480 AC: 7 AN: 1459834 Hom.: 0 Cov.: 30 AF XY: 0.00000551 AC XY: 4 AN XY: 726248

African (AFR) AF: 0.00 AC: 0 AN: 33290

American (AMR) AF: 0.00 AC: 0 AN: 44636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26070

East Asian (EAS) AF: 0.00 AC: 0 AN: 39556

South Asian (SAS) AF: 0.00 AC: 0 AN: 86202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53320

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1110708

Other (OTH) AF: 0.0000166 AC: 1 AN: 60294

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151206 Hom.: 0 Cov.: 32 AF XY: 0.0000271 AC XY: 2 AN XY: 73808

African (AFR) AF: 0.00 AC: 0 AN: 40896

American (AMR) AF: 0.00 AC: 0 AN: 15132

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10510

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000295 AC: 2 AN: 67902

Other (OTH) AF: 0.00 AC: 0 AN: 2080

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	11
DANN	Uncertain	0.99
DEOGEN2	Benign	0.069	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		1.1
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.18
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.037	D
Polyphen		0.80	P
Vest4		0.29
MVP		0.55
MPC		0.24
ClinPred		0.60	D
GERP RS		2.0
PromoterAI		-0.042	Neutral
Varity_R		0.032
gMVP		0.34
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs370026617; hg19: chr1-196857321;