16-29816899-T-A

Variant names:

• chr16-29816899-T-A
• rs868558474
• NM_024516.4:c.374T>A

Variant summary

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

The NM_024516.4(PAGR1):​c.374T>A​(p.Leu125Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000213 in 1,410,268 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. L125P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PAGR1 NM_024516.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.56
• Publications: 0 publications found

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:):

MVP-DT (HGNC:56029): (MVP divergent transcript)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024516.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAGR1	NM_024516.4	MANE Select	c.374T>A	p.Leu125Gln	missense	Exon 1 of 3	NP_078792.1	Q9BTK6
	MVP-DT	NR_186424.1		n.246+2641A>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAGR1	ENST00000320330.8	TSL:1 MANE Select	c.374T>A	p.Leu125Gln	missense	Exon 1 of 3	ENSP00000326519.6	Q9BTK6
	ENSG00000280893	ENST00000609618.2	TSL:5	n.*315T>A		non_coding_transcript_exon	Exon 4 of 6	ENSP00000476774.2	A0A0G2JLL6
	ENSG00000280893	ENST00000609618.2	TSL:5	n.*315T>A		3_prime_UTR	Exon 4 of 6	ENSP00000476774.2	A0A0G2JLL6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000213 AC: 3 AN: 1410268 Hom.: 0 Cov.: 31 AF XY: 0.00000287 AC XY: 2 AN XY: 697788

African (AFR) AF: 0.00 AC: 0 AN: 32436

American (AMR) AF: 0.00 AC: 0 AN: 37786

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25358

East Asian (EAS) AF: 0.00 AC: 0 AN: 37178

South Asian (SAS) AF: 0.00 AC: 0 AN: 81142

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43978

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5678

European-Non Finnish (NFE) AF: 0.00000276 AC: 3 AN: 1088178

Other (OTH) AF: 0.00 AC: 0 AN: 58534

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.099
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.73	D
MetaSVM	Benign	-0.68	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		1.6
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.35	T
Polyphen		0.97	D
Vest4		0.74
MutPred		0.15		Gain of solvent accessibility (P = 0.0137)
MVP		0.66
ClinPred		0.99	D
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.24
gMVP		0.73
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs868558474; hg19: chr16-29828220;