NM_016556.4:c.487T>A

Variant names:

• chr17-42573361-A-T
• rs2292754
• NM_016556.4:c.487T>A

Variant summary

Our verdict is Benign. The variant received -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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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:3
• Conservation: PhyloP100: 2.27
• Publications: 14 publications found

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]

MLX (HGNC:11645): (MAX dimerization protein MLX) The product of this gene belongs to the family of basic helix-loop-helix leucine zipper (bHLH-Zip) transcription factors. These factors form heterodimers with Mad proteins and play a role in proliferation, determination and differentiation. This gene product may act to diversify Mad family function by its restricted association with a subset of the Mad family of transcriptional repressors, namely, Mad1 and Mad4. Alternatively spliced transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 516592.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.147 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016556.4. 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
	PSMC3IP	NM_016556.4	MANE Select	c.487T>A	p.Tyr163Asn	missense	Exon 6 of 8	NP_057640.1	Q9P2W1-1
	PSMC3IP	NM_013290.7		c.451T>A	p.Tyr151Asn	missense	Exon 6 of 8	NP_037422.2
	PSMC3IP	NM_001256014.2		c.298T>A	p.Tyr100Asn	missense	Exon 5 of 7	NP_001242943.1	K7ERB6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSMC3IP	ENST00000393795.8	TSL:1 MANE Select	c.487T>A	p.Tyr163Asn	missense	Exon 6 of 8	ENSP00000377384.2	Q9P2W1-1
	PSMC3IP	ENST00000253789.9	TSL:1	c.451T>A	p.Tyr151Asn	missense	Exon 6 of 8	ENSP00000253789.4	Q9P2W1-2
	PSMC3IP	ENST00000587209.5	TSL:1	c.298T>A	p.Tyr100Asn	missense	Exon 5 of 7	ENSP00000468188.1	K7ERB6

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

GnomAD2 exomes AF: 0.0364 AC: 9145 AN: 251440 AF XY: 0.0353

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 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

African (AFR) AF: 0.119 AC: 3994 AN: 33480

American (AMR) AF: 0.0379 AC: 1697 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000383 AC: 10 AN: 26136

East Asian (EAS) AF: 0.131 AC: 5201 AN: 39700

South Asian (SAS) AF: 0.0736 AC: 6345 AN: 86258

European-Finnish (FIN) AF: 0.0132 AC: 704 AN: 53384

Middle Eastern (MID) AF: 0.0109 AC: 63 AN: 5768

European-Non Finnish (NFE) AF: 0.00283 AC: 3151 AN: 1112010

Other (OTH) AF: 0.0263 AC: 1587 AN: 60396

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

African (AFR) AF: 0.110 AC: 4582 AN: 41472

American (AMR) AF: 0.0271 AC: 415 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.156 AC: 810 AN: 5182

South Asian (SAS) AF: 0.0789 AC: 380 AN: 4816

European-Finnish (FIN) AF: 0.0139 AC: 147 AN: 10586

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00296 AC: 201 AN: 68014

Other (OTH) AF: 0.0369 AC: 78 AN: 2112

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		2.3
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.12
Sift	Benign	0.14	T
Sift4G	Benign	0.39	T
Polyphen		0.028	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
Mutation Taster		=86/14	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2292754; hg19: chr17-40725379; COSMIC: COSV107207282; COSMIC: COSV107207282;