chr17-42573621-G-A

Variant names:

• chr17-42573621-G-A
• rs2093052519
• NM_016556.4:c.340C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_016556.4(PSMC3IP):​c.340C>T​(p.Leu114Phe) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000479 in 1,461,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. 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. L114V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: PSMC3IP NM_016556.4 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.72
• Publications: 0 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]

PSMC3IP Gene-Disease associations (from GenCC):

• ovarian dysgenesis 3

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 46 XX gonadal dysgenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.788

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.340C>T	p.Leu114Phe	missense splice_region	Exon 5 of 8	NP_057640.1	Q9P2W1-1
	PSMC3IP	NM_001256014.2		c.151C>T	p.Leu51Phe	missense splice_region	Exon 4 of 7	NP_001242943.1	K7ERB6
	PSMC3IP	NM_001256015.2		c.103C>T	p.Leu35Phe	missense splice_region	Exon 5 of 8	NP_001242944.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSMC3IP	ENST00000393795.8	TSL:1 MANE Select	c.340C>T	p.Leu114Phe	missense splice_region	Exon 5 of 8	ENSP00000377384.2	Q9P2W1-1
	PSMC3IP	ENST00000587209.5	TSL:1	c.151C>T	p.Leu51Phe	missense splice_region	Exon 4 of 7	ENSP00000468188.1	K7ERB6
	PSMC3IP	ENST00000590760.5	TSL:1	c.-36C>T		splice_region	Exon 4 of 7	ENSP00000466381.1	Q9P2W1-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461790 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 727208

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111928

Other (OTH) AF: 0.00 AC: 0 AN: 60394

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000406424), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.85	D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Benign	-0.51	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		4.7
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.26
Sift	Benign	0.079	T
Sift4G	Uncertain	0.018	D
Polyphen		0.99	D
Vest4		0.73
MutPred		0.67		Gain of methylation at K115 (P = 0.0323)
MVP		0.89
MPC		0.65
ClinPred		0.96	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.34
gMVP		0.55
Mutation Taster		=51/49	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2093052519; hg19: chr17-40725639;