rs766299098

Variant names:

• chr19-43578676-T-A
• rs766299098
• NM_001193621.3:c.157T>A

Your query was ambiguous. Multiple possible variants found:

• chr19-43578676-T-A
• chr19-43578676-T-C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001193621.3(PINLYP):​c.157T>A​(p.Cys53Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000723 in 1,383,530 control chromosomes in the GnomAD database, including 1 homozygotes. 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C53R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000072 (1 hom.)
• Consequence: PINLYP NM_001193621.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.04
• Publications: 0 publications found

Genes affected

PINLYP (HGNC:44206): (phospholipase A2 inhibitor and LY6/PLAUR domain containing) Predicted to enable phospholipase inhibitor activity. Predicted to be involved in negative regulation of catalytic activity. Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000268361 (HGNC:):

XRCC1 (HGNC:12828): (X-ray repair cross complementing 1) The protein encoded by this gene is involved in the efficient repair of DNA single-strand breaks formed by exposure to ionizing radiation and alkylating agents. This protein interacts with DNA ligase III, polymerase beta and poly (ADP-ribose) polymerase to participate in the base excision repair pathway. It may play a role in DNA processing during meiogenesis and recombination in germ cells. A rare microsatellite polymorphism in this gene is associated with cancer in patients of varying radiosensitivity. [provided by RefSeq, Jul 2008]

XRCC1 Gene-Disease associations (from GenCC):

• head and neck cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• spinocerebellar ataxia, autosomal recessive 26

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.948

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001193621.3. 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
	PINLYP	NM_001193621.3	MANE Select	c.157T>A	p.Cys53Ser	missense	Exon 3 of 6	NP_001180550.2	A6NC86-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PINLYP	ENST00000599207.6	TSL:5 MANE Select	c.157T>A	p.Cys53Ser	missense	Exon 3 of 6	ENSP00000469886.1	A6NC86-1
	ENSG00000268361	ENST00000594374.1	TSL:3	c.168+14192A>T		intron	N/A	ENSP00000472698.1	M0R2N6
	PINLYP	ENST00000612042.4	TSL:5	c.229T>A	p.Cys77Ser	missense	Exon 3 of 6	ENSP00000479240.1	A6NC86-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000723 AC: 10 AN: 1383530 Hom.: 1 Cov.: 32 AF XY: 0.0000132 AC XY: 9 AN XY: 682726

African (AFR) AF: 0.00 AC: 0 AN: 31592

American (AMR) AF: 0.00 AC: 0 AN: 35692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25172

East Asian (EAS) AF: 0.00 AC: 0 AN: 35718

South Asian (SAS) AF: 0.000126 AC: 10 AN: 79230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33858

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078694

Other (OTH) AF: 0.00 AC: 0 AN: 57880

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000507 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Uncertain	23
DANN	Benign	0.97
DEOGEN2	Uncertain	0.49	T
Eigen	Uncertain	0.32
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.40	T
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Benign	-0.35	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		3.0
PrimateAI	Benign	0.40	T
Sift4G	Pathogenic	0.0	D
Vest4		0.87
MVP		0.39
ClinPred		0.54	D
GERP RS		4.0
Varity_R		0.29
gMVP		1.0
Mutation Taster		=73/27	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs766299098; hg19: chr19-44082828;