dbSNP rs1361024832: PATL2:p.Tyr217His (chr15-44672023-A-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PM5PP3_Moderate

The ENST00000682850.1(PATL2):c.649T>C(p.Tyr217His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,399,370 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. Y217N) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

PATL2
ENST00000682850.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.68

Publications

0 publications found

Variant links:

Genes affected

PATL2 (HGNC:33630): (PAT1 homolog 2) Predicted to enable RNA binding activity. Predicted to be involved in P-body assembly and deadenylation-dependent decapping of nuclear-transcribed mRNA. Predicted to act upstream of or within negative regulation of cytoplasmic mRNA processing body assembly. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

PATL2 Gene-Disease associations (from GenCC):

oocyte maturation defect 4
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

PATL2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr15-44672023-A-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 549488.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.919

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000682850.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PATL2	NM_001387263.1	MANE Select	c.649T>C	p.Tyr217His	missense	Exon 9 of 18	NP_001374192.1
PATL2	NM_001145112.2		c.649T>C	p.Tyr217His	missense	Exon 7 of 16	NP_001138584.1
PATL2	NM_001387261.1		c.649T>C	p.Tyr217His	missense	Exon 7 of 16	NP_001374190.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PATL2	ENST00000682850.1	MANE Select	c.649T>C	p.Tyr217His	missense	Exon 9 of 18	ENSP00000508024.1
PATL2	ENST00000434130.6	TSL:5	c.649T>C	p.Tyr217His	missense	Exon 7 of 16	ENSP00000416673.1
PATL2	ENST00000560780.1	TSL:2	c.82T>C	p.Tyr28His	missense	Exon 6 of 15	ENSP00000453695.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.15e-7

AC:

AN:

1399370

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

690194

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

31598

American (AMR)

AF:

0.00

AC:

AN:

35704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25182

East Asian (EAS)

AF:

0.00

AC:

AN:

35738

South Asian (SAS)

AF:

0.00

AC:

AN:

79236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49276

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

9.27e-7

AC:

AN:

1078938

Other (OTH)

AF:

0.00

AC:

AN:

58000

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.87

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.92

MetaSVM

Uncertain

0.59

MutationAssessor

Pathogenic

3.0

PhyloP100

8.7

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-4.9

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.87

MutPred

0.75

Loss of phosphorylation at Y217 (P = 0.0161)

MVP

0.48

MPC

0.00034

ClinPred

1.0

GERP RS

5.7

Varity_R

0.64

gMVP

0.70

Mutation Taster

=37/63

disease causing

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over