16-29816536-C-T

Position:

• chr16-29816536-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_024516.4(PAGR1):​c.11C>T​(p.Ala4Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000516 in 1,355,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000052 (0 hom.)
• Consequence: PAGR1 NM_024516.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.38

Genes affected

PAGR1 (HGNC:28707): (PAXIP1 associated glutamate rich protein 1) Enables estrogen receptor binding activity. Involved in positive regulation of cell cycle G1/S phase transition; positive regulation of intracellular estrogen receptor signaling pathway; and positive regulation of transcription by RNA polymerase II. Located in nucleus. Part of MLL3/4 complex. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000280893 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.023161769).
• BP6: Variant 16-29816536-C-T is Benign according to our data. Variant chr16-29816536-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2599510.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAGR1	NM_024516.4	c.11C>T	p.Ala4Val	missense_variant	1/3	ENST00000320330.8	NP_078792.1
MVP-DT	NR_186424.1	n.246+3004G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAGR1	ENST00000320330.8	c.11C>T	p.Ala4Val	missense_variant	1/3	1	NM_024516.4	ENSP00000326519.6
ENSG00000280893	ENST00000609618.2	n.1032C>T		non_coding_transcript_exon_variant	4/6	5		ENSP00000476774.2
MVP-DT	ENST00000569039.5	n.245+3004G>A		intron_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000516 AC: 7 AN: 1355876 Hom.: 0 Cov.: 31 AF XY: 0.00000755 AC XY: 5 AN XY: 662614

Gnomad4 AFR exome AF: 0.000133

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000180

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 25, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	15
DANN	Benign	0.89
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.023	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.14	N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.23	N
REVEL	Benign	0.12
Sift	Benign	1.0	T
Sift4G	Benign	0.15	T
Polyphen		0.0	B
Vest4		0.030
MutPred		0.17		Gain of sheet (P = 0.0221);
MVP		0.043
ClinPred		0.029	T
GERP RS		3.2
Varity_R		0.029
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1265788352; hg19: chr16-29827857;