chr17-42573361-A-T

Position:

• chr17-42573361-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016556.4(PSMC3IP):​c.487T>A​(p.Tyr163Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0182 in 1,614,006 control chromosomes in the GnomAD database, including 1,337 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.043 (351 hom., cov: 32)
  • Exomes 𝑓: 0.016 (986 hom.)
• Consequence: PSMC3IP NM_016556.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.27

Genes affected

PSMC3IP (HGNC:17928): (PSMC3 interacting protein) This gene encodes a protein that functions in meiotic recombination. It is a subunit of the PSMC3IP/MND1 complex, which interacts with PSMC3/TBP1 to stimulate DMC1- and RAD51-mediated strand exchange during meiosis. The protein encoded by this gene can also co-activate ligand-driven transcription mediated by estrogen, androgen, glucocorticoid, progesterone, and thyroid nuclear receptors. Mutations in this gene cause XX female gonadal dysgenesis. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Dec 2011]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019218028).
• BP6: Variant 17-42573361-A-T is Benign according to our data. Variant chr17-42573361-A-T is described in ClinVar as [Benign]. Clinvar id is 516592.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-42573361-A-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.147 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PSMC3IP	NM_016556.4	c.487T>A	p.Tyr163Asn	missense_variant	6/8	ENST00000393795.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSMC3IP	ENST00000393795.8	c.487T>A	p.Tyr163Asn	missense_variant	6/8	1	NM_016556.4	P1

Frequencies

GnomAD3 genomes AF: 0.0435 AC: 6611 AN: 152032 Hom.: 351 Cov.: 32

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0270

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.157

Gnomad SAS AF: 0.0797

Gnomad FIN AF: 0.0139

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00295

Gnomad OTH AF: 0.0373

GnomAD3 exomes AF: 0.0364 AC: 9145 AN: 251440 Hom.: 434 AF XY: 0.0353 AC XY: 4800 AN XY: 135912

Gnomad AFR exome AF: 0.109

Gnomad AMR exome AF: 0.0382

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.165

Gnomad SAS exome AF: 0.0720

Gnomad FIN exome AF: 0.0125

Gnomad NFE exome AF: 0.00362

Gnomad OTH exome AF: 0.0202

GnomAD4 exome AF: 0.0156 AC: 22752 AN: 1461856 Hom.: 986 Cov.: 31 AF XY: 0.0170 AC XY: 12350 AN XY: 727238

Gnomad4 AFR exome AF: 0.119

Gnomad4 AMR exome AF: 0.0379

Gnomad4 ASJ exome AF: 0.000383

Gnomad4 EAS exome AF: 0.131

Gnomad4 SAS exome AF: 0.0736

Gnomad4 FIN exome AF: 0.0132

Gnomad4 NFE exome AF: 0.00283

Gnomad4 OTH exome AF: 0.0263

GnomAD4 genome AF: 0.0435 AC: 6618 AN: 152150 Hom.: 351 Cov.: 32 AF XY: 0.0446 AC XY: 3314 AN XY: 74368

Gnomad4 AFR AF: 0.110

Gnomad4 AMR AF: 0.0271

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.156

Gnomad4 SAS AF: 0.0789

Gnomad4 FIN AF: 0.0139

Gnomad4 NFE AF: 0.00296

Gnomad4 OTH AF: 0.0369

Alfa AF: 0.0128 Hom.: 59

Bravo AF: 0.0481

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.100 AC: 442

ESP6500EA AF: 0.00419 AC: 36

ExAC AF: 0.0379 AC: 4601

Asia WGS AF: 0.101 AC: 352 AN: 3478

EpiCase AF: 0.00262

EpiControl AF: 0.00338

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 07, 2017

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	21
DANN	Benign	0.90
DEOGEN2	Benign	0.16	T;.;T;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.91	D;D;D;D
MetaRNN	Benign	0.0019	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;.;.;.
MutationTaster	Benign	0.0000042	P;P;P;P
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-2.2	N;N;.;.
REVEL	Benign	0.12
Sift	Benign	0.14	T;T;.;.
Sift4G	Benign	0.39	T;T;T;T
Polyphen		0.028	B;B;.;.
Vest4		0.29
MPC		0.38
ClinPred		0.024	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.37
gMVP		0.43

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: rs2292754; hg19: chr17-40725379;