1-196779204-T-G

Position:

• chr1-196779204-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_021023.6(CFHR3):​c.101T>G​(p.Phe34Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00149 in 1,530,158 control chromosomes in the GnomAD database, including 616 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0082 (304 hom., cov: 25)
  • Exomes 𝑓: 0.00083 (312 hom.)
• Consequence: CFHR3 NM_021023.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0310

Genes affected

CFHR3 (HGNC:16980): (complement factor H related 3) The protein encoded by this gene is a secreted protein, which belongs to the complement factor H-related protein family. It binds to heparin, and may be involved in complement regulation. Mutations in this gene are associated with decreased risk of age-related macular degeneration, and with an increased risk of atypical hemolytic-uremic syndrome. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028657913).
• BP6: Variant 1-196779204-T-G is Benign according to our data. Variant chr1-196779204-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 730391.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 = 0.00819 (1126/137424) while in subpopulation AFR AF= 0.0328 (1083/33004). AF 95% confidence interval is 0.0312. There are 304 homozygotes in gnomad4. There are 564 alleles in male gnomad4 subpopulation. Median coverage is 25. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 304 AD,AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFHR3	NM_021023.6	c.101T>G	p.Phe34Cys	missense_variant	2/6	ENST00000367425.9
CFHR3	NM_001166624.2	c.101T>G	p.Phe34Cys	missense_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFHR3	ENST00000367425.9	c.101T>G	p.Phe34Cys	missense_variant	2/6	1	NM_021023.6	P1
CFHR3	ENST00000471440.6	c.101T>G	p.Phe34Cys	missense_variant	2/5	1
CFHR3	ENST00000391985.7	c.101T>G	p.Phe34Cys	missense_variant	2/5	2
CFHR3	ENST00000367427.7	c.101T>G	p.Phe34Cys	missense_variant, NMD_transcript_variant	2/7	5

Frequencies

GnomAD3 genomes AF: 0.00816 AC: 1121 AN: 137304 Hom.: 302 Cov.: 25

Gnomad AFR AF: 0.0328

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00218

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: 0.0000773

Gnomad OTH AF: 0.00379

GnomAD3 exomes AF: 0.00219 AC: 522 AN: 238138 Hom.: 145 AF XY: 0.00145 AC XY: 186 AN XY: 128382

Gnomad AFR exome AF: 0.0355

Gnomad AMR exome AF: 0.000821

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000110

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000461

Gnomad OTH exome AF: 0.000515

GnomAD4 exome AF: 0.000828 AC: 1153 AN: 1392734 Hom.: 312 Cov.: 30 AF XY: 0.000690 AC XY: 477 AN XY: 691674

Gnomad4 AFR exome AF: 0.0343

Gnomad4 AMR exome AF: 0.00100

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000216

Gnomad4 OTH exome AF: 0.00204

GnomAD4 genome AF: 0.00819 AC: 1126 AN: 137424 Hom.: 304 Cov.: 25 AF XY: 0.00843 AC XY: 564 AN XY: 66900

Gnomad4 AFR AF: 0.0328

Gnomad4 AMR AF: 0.00217

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000773

Gnomad4 OTH AF: 0.00374

Alfa AF: 0.000267 Hom.: 2

ESP6500AA AF: 0.0371 AC: 141

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00264 AC: 305

Asia WGS AF: 0.00216 AC: 7 AN: 3258

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Age related macular degeneration 1;C2749604:Hemolytic uremic syndrome, atypical, susceptibility to, 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 27, 2021

- -

Kidney disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	15
DANN	Benign	0.85
DEOGEN2	Benign	0.15	T;T;.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0086	N
LIST_S2	Benign	0.64	T;.;T;T
MetaRNN	Benign	0.0029	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.34	N;.;N;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-4.7	D;D;D;.
REVEL	Benign	0.20
Sift	Pathogenic	0.0	D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.92	P;P;.;.
Vest4		0.12
MVP		0.31
MPC		0.38
ClinPred		0.086	T
GERP RS		1.1
Varity_R		0.32
gMVP		0.87

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

Publications

LitVar

Other links and lift over

dbSNP: rs61737523; hg19: chr1-196748334;