chr4-75012898-G-A

Variant names:

• chr4-75012898-G-A
• rs192705593
• NM_015393.4:c.517G>A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_015393.4(PARM1):​c.517G>A​(p.Val173Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000757 in 1,613,826 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00085 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00075 (2 hom.)
• Consequence: PARM1 NM_015393.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.04

Genes affected

PARM1 (HGNC:24536): (prostate androgen-regulated mucin-like protein 1) Predicted to be involved in positive regulation of telomerase activity. Located in several cellular components, including Golgi apparatus; endosome; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000248165 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0061292946).
• BP6: Variant 4-75012898-G-A is Benign according to our data. Variant chr4-75012898-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2266683.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PARM1	NM_015393.4	c.517G>A	p.Val173Ile	missense_variant	Exon 2 of 4	ENST00000307428.7	NP_056208.2
PARM1	XM_011531833.1	c.622G>A	p.Val208Ile	missense_variant	Exon 3 of 5		XP_011530135.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PARM1	ENST00000307428.7	c.517G>A	p.Val173Ile	missense_variant	Exon 2 of 4	1	NM_015393.4	ENSP00000370224.3
PARM1	ENST00000513238.5	c.44-20985G>A		intron_variant	Intron 1 of 2	3		ENSP00000424276.1
ENSG00000248165	ENST00000513770.1	n.52-13727C>T		intron_variant	Intron 1 of 3	3

Frequencies

GnomAD3 genomes AF: 0.000849 AC: 129 AN: 152000 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000822

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00100

Gnomad OTH AF: 0.00288

GnomAD3 exomes AF: 0.000591 AC: 147 AN: 248934 Hom.: 0 AF XY: 0.000666 AC XY: 90 AN XY: 135058

Gnomad AFR exome AF: 0.000710

Gnomad AMR exome AF: 0.000840

Gnomad ASJ exome AF: 0.0000996

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.000869

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000747 AC: 1092 AN: 1461708 Hom.: 2 Cov.: 55 AF XY: 0.000751 AC XY: 546 AN XY: 727138

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.000939

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.000262

Gnomad4 NFE exome AF: 0.000876

Gnomad4 OTH exome AF: 0.000646

GnomAD4 genome AF: 0.000848 AC: 129 AN: 152118 Hom.: 1 Cov.: 32 AF XY: 0.000874 AC XY: 65 AN XY: 74372

Gnomad4 AFR AF: 0.000820

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00100

Gnomad4 OTH AF: 0.00285

Alfa AF: 0.000913 Hom.: 0

Bravo AF: 0.000876

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000233 AC: 1

ESP6500EA AF: 0.00129 AC: 11

ExAC AF: 0.000561 AC: 68

EpiCase AF: 0.00142

EpiControl AF: 0.00107

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Aug 02, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	0.066
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.045
DANN	Benign	0.49
DEOGEN2	Benign	0.00090	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.30	T
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.11	N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.0050
Sift	Benign	0.59	T
Sift4G	Benign	0.54	T
Polyphen		0.0020	B
Vest4		0.036
MVP		0.11
MPC		0.11
ClinPred		0.000088	T
GERP RS		-4.2
Varity_R		0.0098
gMVP		0.059

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: rs192705593; hg19: chr4-75938108;