C1R p.Val50Asp

Variant names:

• chr12-7091534-A-T
• NM_001733.7:c.149T>A
• C1R p.Val50Asp

Your query was ambiguous. Multiple possible variants found:

• chr12-7091534-A-T
• chr12-7091533-GA-AT

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PS1 PM2 PP3_Strong

The NM_001733.7(C1R):​c.149T>A​(p.Val50Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 10/17 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Synonymous variant affecting the same amino acid position (i.e. V50V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: C1R NM_001733.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.74
• Publications: 5 publications found

Genes affected

C1R (HGNC:1246): (complement C1r) This gene encodes a member of the peptidase S1 protein family. The encoded protein is a proteolytic subunit in the complement system C1 complex. The complement system acts as a mediator in the innate immune response by ultimately triggering phagocytosis, inflammation, and rupturing the bacterial cell wall. Mutations in this gene are associated with Ehlers-Danlos Syndrome. [provided by RefSeq, Dec 2018]

C1RL (HGNC:21265): (complement C1r subcomponent like) Predicted to enable serine-type endopeptidase activity. Predicted to be involved in zymogen activation. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PS1: Transcript NM_001733.7 (C1R) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001733.7. 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
	C1R	NM_001733.7	MANE Select	c.149T>A	p.Val50Asp	missense	Exon 2 of 11	NP_001724.4	A0A3B3ISR2
	C1R	NM_001354346.2		c.191T>A	p.Val64Asp	missense	Exon 2 of 11	NP_001341275.1	B4DPQ0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C1R	ENST00000647956.2	MANE Select	c.149T>A	p.Val50Asp	missense	Exon 2 of 11	ENSP00000497341.1	A0A3B3ISR2
	C1R	ENST00000536092.1	TSL:1	n.254T>A		non_coding_transcript_exon	Exon 2 of 2
	C1R	ENST00000903851.1		c.302T>A	p.Val101Asp	missense	Exon 3 of 12	ENSP00000573910.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Benign	-0.48	T
PhyloP100		5.7
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
PromoterAI		0.0048	Neutral
gMVP		0.92
Mutation Taster		=85/15	disease causing (ClinVar)

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr12-7244130;