5-75677796-T-G

Variant names:

• chr5-75677796-T-G
• rs1408846041
• NM_001099271.2:c.1562A>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001099271.2(POC5):​c.1562A>C​(p.Glu521Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,456,808 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. E521G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: POC5 NM_001099271.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.01
• Publications: 0 publications found

Genes affected

POC5 (HGNC:26658): (POC5 centriolar protein) Predicted to enable identical protein binding activity. Located in centrosome; cytosol; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ANKDD1B (HGNC:32525): (ankyrin repeat and death domain containing 1B) Predicted to be involved in signal transduction. [provided by Alliance of Genome Resources, Apr 2022]

ANKDD1B Gene-Disease associations (from GenCC):

• ankylosing spondylitis

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.814

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001099271.2. 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
	POC5	NM_001099271.2	MANE Select	c.1562A>C	p.Glu521Ala	missense	Exon 11 of 12	NP_001092741.1	Q8NA72-1
	POC5	NM_152408.3		c.1487A>C	p.Glu496Ala	missense	Exon 10 of 11	NP_689621.2	Q8NA72-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POC5	ENST00000428202.7	TSL:1 MANE Select	c.1562A>C	p.Glu521Ala	missense	Exon 11 of 12	ENSP00000410216.2	Q8NA72-1
	POC5	ENST00000446329.6	TSL:1	c.1487A>C	p.Glu496Ala	missense	Exon 10 of 11	ENSP00000399481.2	Q8NA72-3
	POC5	ENST00000930836.1		c.1682A>C	p.Glu561Ala	missense	Exon 12 of 13	ENSP00000600895.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1456808 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 724630

African (AFR) AF: 0.0000302 AC: 1 AN: 33162

American (AMR) AF: 0.00 AC: 0 AN: 43860

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25972

East Asian (EAS) AF: 0.00 AC: 0 AN: 39466

South Asian (SAS) AF: 0.00 AC: 0 AN: 85396

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53258

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109778

Other (OTH) AF: 0.00 AC: 0 AN: 60166

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.052	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	-0.070	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		6.0
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-4.2	D
REVEL	Uncertain	0.51
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.51		Loss of catalytic residue at E521 (P = 0.0583)
MVP		0.86
MPC		0.37
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.72
gMVP		0.49
Mutation Taster		=79/21	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1408846041; hg19: chr5-74973621;