rs879255637

Variant names:

• chr9-130664744-G-C
• rs879255637
• NM_021619.3:c.91G>C

Your query was ambiguous. Multiple possible variants found:

• chr9-130664744-G-C
• chr9-130664744-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PM5 BP4

The NM_021619.3(PRDM12):​c.91G>C​(p.Asp31His) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,610,668 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. D31Y) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PRDM12 NM_021619.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.88
• Publications: 3 publications found

Genes affected

PRDM12 (HGNC:13997): (PR/SET domain 12) This gene encodes a transcriptional regulator of sensory neuronal specification that plays a critical role in pain perception. The encoded protein contains an N-terminal PRDI-BF1 and RIZ homology (PR) domain, a SET domain, and three C-terminal C2H2 zinc finger DNA-binding domains. Naturally occurring mutations in this gene are associated with congenital insensitivity to pain (CIP), and hereditary sensory and autonomic neuropathies (HSAN's) affecting peripheral sensory and autonomic neurons. Deregulation of this gene is associated with solid cancers and hematological malignancies including chronic myeloid leukaemia. [provided by RefSeq, Mar 2017]

PRDM12 Gene-Disease associations (from GenCC):

• congenital insensitivity to pain-hypohidrosis syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• hereditary sensory and autonomic neuropathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: Illumina

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-130664744-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 253120.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.4073192).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021619.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRDM12	NM_021619.3	MANE Select	c.91G>C	p.Asp31His	missense	Exon 1 of 5	NP_067632.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRDM12	ENST00000253008.3	TSL:1 MANE Select	c.91G>C	p.Asp31His	missense	Exon 1 of 5	ENSP00000253008.2
	PRDM12	ENST00000676323.1		c.91G>C	p.Asp31His	missense	Exon 1 of 6	ENSP00000502471.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1458486 Hom.: 0 Cov.: 34 AF XY: 0.00000276 AC XY: 2 AN XY: 725546

African (AFR) AF: 0.00 AC: 0 AN: 33432

American (AMR) AF: 0.00 AC: 0 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.00 AC: 0 AN: 86072

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5092

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111644

Other (OTH) AF: 0.00 AC: 0 AN: 60204

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152182 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74336

African (AFR) AF: 0.00 AC: 0 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Benign	0.045	T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.095	D
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L
PhyloP100		5.9
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.44
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.27
MutPred		0.50		Loss of loop (P = 0.0288)
MVP		0.42
MPC		2.1
ClinPred		0.93	D
GERP RS		4.5
PromoterAI		0.19	Neutral
Varity_R		0.50
gMVP		0.87
Mutation Taster		=30/70	disease causing

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: rs879255637; hg19: chr9-133540131;