rs376684550

Variant names:

• chr1-45727786-C-G
• rs376684550
• NM_005897.3:c.893G>C

Your query was ambiguous. Multiple possible variants found:

• chr1-45727786-C-G
• chr1-45727786-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005897.3(IPP):​c.893G>C​(p.Arg298Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000431 in 1,393,448 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R298W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: IPP NM_005897.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.87
• Publications: 0 publications found

Genes affected

IPP (HGNC:6108): (intracisternal A particle-promoted polypeptide) The protein encoded by this gene is a member of the kelch family of proteins, which is characterized by a 50 amino acid repeat which interacts with actin. Transcript variants have been described but their full-length nature has not been determined. [provided by RefSeq, Jul 2008]

ENSG00000302565 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.846

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005897.3. 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
	IPP	NM_005897.3	MANE Select	c.893G>C	p.Arg298Pro	missense	Exon 5 of 9	NP_005888.1	Q9Y573-1
	IPP	NM_001145349.2		c.893G>C	p.Arg298Pro	missense	Exon 5 of 10	NP_001138821.1	Q9Y573-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IPP	ENST00000396478.4	TSL:2 MANE Select	c.893G>C	p.Arg298Pro	missense	Exon 5 of 9	ENSP00000379739.3	Q9Y573-1
	IPP	ENST00000359942.8	TSL:1	c.893G>C	p.Arg298Pro	missense	Exon 5 of 10	ENSP00000353024.4	Q9Y573-2
	IPP	ENST00000890995.1		c.893G>C	p.Arg298Pro	missense	Exon 6 of 10	ENSP00000561054.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000431 AC: 6 AN: 1393448 Hom.: 0 Cov.: 30 AF XY: 0.00000729 AC XY: 5 AN XY: 686200

African (AFR) AF: 0.00 AC: 0 AN: 32642

American (AMR) AF: 0.00 AC: 0 AN: 42784

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24716

East Asian (EAS) AF: 0.00 AC: 0 AN: 38782

South Asian (SAS) AF: 0.00 AC: 0 AN: 75688

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51316

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5478

European-Non Finnish (NFE) AF: 0.00000563 AC: 6 AN: 1064974

Other (OTH) AF: 0.00 AC: 0 AN: 57068

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.089	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	0.0057	D
MutationAssessor	Benign	1.5	L
PhyloP100		5.9
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.015	D
Polyphen		0.99	D
Vest4		0.90
MutPred		0.62		Loss of MoRF binding (P = 0.0011)
MVP		0.91
MPC		0.70
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.87
gMVP		0.88
Mutation Taster		=48/52	disease causing

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

Other links and lift over

dbSNP: rs376684550; hg19: chr1-46193458;