16-11273419-C-G

Variant names:

• chr16-11273419-C-G
• rs1395011231
• NM_021247.3:c.177G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021247.3(PRM3):​c.177G>C​(p.Glu59Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000525 in 152,358 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.000053 (0 hom., cov: 34)
• Consequence: PRM3 NM_021247.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.28

Genes affected

PRM3 (HGNC:13732): (protamine 3) Predicted to enable DNA binding activity. Predicted to be involved in flagellated sperm motility. Predicted to be located in nucleus. Predicted to be part of nucleosome. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

RMI2 (HGNC:28349): (RecQ mediated genome instability 2) RMI2 is a component of the BLM (RECQL3; MIM 604610) complex, which plays a role in homologous recombination-dependent DNA repair and is essential for genome stability (Xu et al., 2008 [PubMed 18923082]).[supplied by OMIM, Nov 2008]

LOC105371082 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07469213).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRM3	NM_021247.3	c.177G>C	p.Glu59Asp	missense_variant	Exon 1 of 1	ENST00000327157.4	NP_067070.2
LOC105371082	XR_933070.4	n.178+23641C>G		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRM3	ENST00000327157.4	c.177G>C	p.Glu59Asp	missense_variant	Exon 1 of 1	6	NM_021247.3	ENSP00000325638.2
RMI2	ENST00000572173.1	c.-515-21797C>G		intron_variant	Intron 1 of 4	1		ENSP00000461206.1
RMI2	ENST00000573910.1	n.160+23641C>G		intron_variant	Intron 1 of 1	3
RMI2	ENST00000649869.1	n.152+23641C>G		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes AF: 0.0000525 AC: 8 AN: 152240 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 36

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152358 Hom.: 0 Cov.: 34 AF XY: 0.0000537 AC XY: 4 AN XY: 74506

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000264

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.177G>C (p.E59D) alteration is located in exon 1 (coding exon 1) of the PRM3 gene. This alteration results from a G to C substitution at nucleotide position 177, causing the glutamic acid (E) at amino acid position 59 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	0.31
DANN	Uncertain	0.98
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.14	N
MetaRNN	Benign	0.075	T
MetaSVM	Benign	-1.1	T
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.4	N
REVEL	Benign	0.047
Sift	Benign	0.16	T
Sift4G	Pathogenic	0.0	D
Vest4		0.19
MutPred		0.13		Gain of loop (P = 0.0097);
MVP		0.055
ClinPred		0.59	D
GERP RS		-0.81
gMVP		0.011

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

Publications

LitVar

Other links and lift over

dbSNP: rs1395011231; hg19: chr16-11367276;