chr19-43577136-A-G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001193621.3(PINLYP):​c.-56A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.791 in 1,535,394 control chromosomes in the GnomAD database, including 481,132 homozygotes. 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: 𝑓 0.80 (49341 hom., cov: 29)
  • Exomes 𝑓: 0.79 (431791 hom.)
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.5421614E-7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.862 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PINLYP	NM_001193621.3	c.-56A>G		5_prime_UTR_variant	Exon 2 of 6	ENST00000599207.6	NP_001180550.2
PINLYP	XM_047438830.1	c.17A>G	p.His6Arg	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>G		5_prime_UTR_variant	Exon 2 of 6	5	NM_001193621.3	ENSP00000469886.1
ENSG00000268361	ENST00000594374.1	c.168+15732T>C		intron_variant	Intron 1 of 2	3		ENSP00000472698.1

Frequencies

GnomAD3 genomes AF: 0.805 AC: 122261 AN: 151898 Hom.: 49314 Cov.: 29

Gnomad AFR AF: 0.826

Gnomad AMI AF: 0.838

Gnomad AMR AF: 0.870

Gnomad ASJ AF: 0.815

Gnomad EAS AF: 0.883

Gnomad SAS AF: 0.775

Gnomad FIN AF: 0.736

Gnomad MID AF: 0.854

Gnomad NFE AF: 0.783

Gnomad OTH AF: 0.812

GnomAD2 exomes AF: 0.817 AC: 109751 AN: 134352 AF XY: 0.811

Gnomad AFR exome AF: 0.826

Gnomad AMR exome AF: 0.903

Gnomad ASJ exome AF: 0.809

Gnomad EAS exome AF: 0.884

Gnomad FIN exome AF: 0.747

Gnomad NFE exome AF: 0.787

Gnomad OTH exome AF: 0.823

GnomAD4 exome AF: 0.789 AC: 1091588 AN: 1383378 Hom.: 431791 Cov.: 50 AF XY: 0.788 AC XY: 537711 AN XY: 682630

African (AFR) AF: 0.823 AC: 26000 AN: 31584

American (AMR) AF: 0.898 AC: 32057 AN: 35694

Ashkenazi Jewish (ASJ) AF: 0.817 AC: 20562 AN: 25174

East Asian (EAS) AF: 0.893 AC: 31901 AN: 35732

South Asian (SAS) AF: 0.779 AC: 61737 AN: 79204

European-Finnish (FIN) AF: 0.737 AC: 24984 AN: 33878

Middle Eastern (MID) AF: 0.860 AC: 4851 AN: 5638

European-Non Finnish (NFE) AF: 0.782 AC: 843186 AN: 1078598

Other (OTH) AF: 0.800 AC: 46310 AN: 57876

GnomAD4 genome AF: 0.805 AC: 122344 AN: 152016 Hom.: 49341 Cov.: 29 AF XY: 0.805 AC XY: 59820 AN XY: 74322

African (AFR) AF: 0.825 AC: 34207 AN: 41438

American (AMR) AF: 0.871 AC: 13290 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.815 AC: 2829 AN: 3470

East Asian (EAS) AF: 0.883 AC: 4563 AN: 5168

South Asian (SAS) AF: 0.775 AC: 3728 AN: 4808

European-Finnish (FIN) AF: 0.736 AC: 7784 AN: 10574

Middle Eastern (MID) AF: 0.850 AC: 250 AN: 294

European-Non Finnish (NFE) AF: 0.783 AC: 53217 AN: 67978

Other (OTH) AF: 0.811 AC: 1713 AN: 2112

Alfa AF: 0.792 Hom.: 87868

Bravo AF: 0.821

TwinsUK AF: 0.787 AC: 2920

ALSPAC AF: 0.771 AC: 2973

ExAC AF: 0.758 AC: 10975

Asia WGS AF: 0.808 AC: 2808 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	16
DANN	Benign	0.74
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.0065	N
LIST_S2	Benign	0.20	T
MetaRNN	Benign	6.5e-7	T
MetaSVM	Benign	-0.96	T
PhyloP100		1.3
PrimateAI	Benign	0.32	T
Sift4G	Benign	1.0	T
Vest4		0.028
ClinPred		0.061	T
GERP RS		0.73
PromoterAI		0.13	Neutral
gMVP		0.44

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: rs2682585; hg19: chr19-44081288; COSMIC: COSV107299612; COSMIC: COSV107299612;