19-43577136-A-T

Variant names:

• chr19-43577136-A-T
• rs2682585
• NM_001193621.3:c.-56A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001193621.3(PINLYP):​c.-56A>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 29)
• Consequence: PINLYP NM_001193621.3 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.26
• Publications: 54 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19022405).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PINLYP	NM_001193621.3	c.-56A>T		5_prime_UTR_variant	Exon 2 of 6	ENST00000599207.6	NP_001180550.2
PINLYP	XM_047438830.1	c.17A>T	p.His6Leu	missense_variant	Exon 1 of 5		XP_047294786.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PINLYP	ENST00000599207.6	c.-56A>T		5_prime_UTR_variant	Exon 2 of 6	5	NM_001193621.3	ENSP00000469886.1
ENSG00000268361	ENST00000594374.1	c.168+15732T>A		intron_variant	Intron 1 of 2	3		ENSP00000472698.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 50

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.086	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	15
DANN	Benign	0.94
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.20	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.82	T
PhyloP100		1.3
PrimateAI	Benign	0.31	T
Sift4G	Benign	0.13	T
Vest4		0.24
MVP		0.45
ClinPred		0.66	D
GERP RS		0.73
PromoterAI		-0.035	Neutral
gMVP		0.56
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2682585; hg19: chr19-44081288;