rs970486399

Variant names:

• chr4-120695142-A-G
• rs970486399
• NM_018699.4:c.1862T>C

Your query was ambiguous. Multiple possible variants found:

• chr4-120695142-A-G
• chr4-120695142-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_018699.4(PRDM5):​c.1862T>C​(p.Met621Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,034 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M621V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: PRDM5 NM_018699.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 6.95
• Publications: 0 publications found

Genes affected

PRDM5 (HGNC:9349): (PR/SET domain 5) The protein encoded by this gene is a transcription factor of the PR-domain protein family. It contains a PR-domain and multiple zinc finger motifs. Transcription factors of the PR-domain family are known to be involved in cell differentiation and tumorigenesis. [provided by RefSeq, Jul 2008]

PRDM5 Gene-Disease associations (from GenCC):

• brittle cornea syndrome 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics, G2P
• brittle cornea syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• aortic disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• Axenfeld-Rieger syndrome

  Inheritance: AD Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018699.4. 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
	PRDM5	NM_018699.4	MANE Select	c.1862T>C	p.Met621Thr	missense	Exon 16 of 16	NP_061169.2
	PRDM5	NM_001379104.1		c.1895T>C	p.Met632Thr	missense	Exon 16 of 16	NP_001366033.1
	PRDM5	NM_001300823.2		c.1769T>C	p.Met590Thr	missense	Exon 15 of 15	NP_001287752.1	Q9NQX1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRDM5	ENST00000264808.8	TSL:1 MANE Select	c.1862T>C	p.Met621Thr	missense	Exon 16 of 16	ENSP00000264808.3	Q9NQX1-1
	PRDM5	ENST00000428209.6	TSL:1	c.1769T>C	p.Met590Thr	missense	Exon 15 of 15	ENSP00000404832.2	Q9NQX1-2
	PRDM5	ENST00000515109.5	TSL:1	c.*177T>C		3_prime_UTR	Exon 14 of 14	ENSP00000422309.1	Q9NQX1-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000797 AC: 2 AN: 251020 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461034 Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5 AN XY: 726840

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

American (AMR) AF: 0.0000447 AC: 2 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111340

Other (OTH) AF: 0.00 AC: 0 AN: 60356

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.058	T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.040	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Benign	-0.39	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		6.9
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.31
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.054	T
Polyphen		0.99	D
Vest4		0.56
MutPred		0.57		Loss of stability (P = 0.0135)
MVP		0.33
MPC		0.66
ClinPred		0.84	D
GERP RS		5.6
Varity_R		0.38
gMVP		0.67
Mutation Taster		=58/42	polymorphism

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: rs970486399; hg19: chr4-121616297;