chr16-29819695-G-T

Position:

• chr16-29819695-G-T

Variant summary

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

The NM_024516.4(PAGR1):​c.706G>T​(p.Ala236Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,492 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PAGR1 NM_024516.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.18

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]

ENSG00000281348 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.018319339).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAGR1	NM_024516.4	c.706G>T	p.Ala236Ser	missense_variant	3/3	ENST00000320330.8	NP_078792.1
MVP-DT	NR_186424.1	n.185-94C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAGR1	ENST00000320330.8	c.706G>T	p.Ala236Ser	missense_variant	3/3	1	NM_024516.4	ENSP00000326519.6
ENSG00000281348	ENST00000562285.1	n.193G>T		non_coding_transcript_exon_variant	2/3	2		ENSP00000457363.1
ENSG00000280893	ENST00000609618.2	n.*647G>T		non_coding_transcript_exon_variant	6/6	5		ENSP00000476774.2
ENSG00000280893	ENST00000609618.2	n.*647G>T		3_prime_UTR_variant	6/6	5		ENSP00000476774.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461492 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727052

Gnomad4 AFR exome AF: 0.00

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000363 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2024

The c.706G>T (p.A236S) alteration is located in exon 3 (coding exon 3) of the PAGR1 gene. This alteration results from a G to T substitution at nucleotide position 706, causing the alanine (A) at amino acid position 236 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.0090
DANN	Benign	0.77
DEOGEN2	Benign	0.099	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.079	N
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.0020	T
MetaRNN	Benign	0.018	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.40	N
REVEL	Benign	0.023
Sift	Benign	0.76	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.078
MVP		0.12
ClinPred		0.032	T
GERP RS		-8.5
Varity_R		0.047
gMVP		0.035

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

LitVar

Other links and lift over

dbSNP: rs756602095; hg19: chr16-29831016;