chr21-44856223-C-G

Variant names:

• chr21-44856223-C-G
• NM_004339.4:c.419G>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004339.4(PTTG1IP):​c.419G>C​(p.Arg140Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PTTG1IP NM_004339.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.596

Genes affected

PTTG1IP (HGNC:13524): (PTTG1 interacting protein) This gene encodes a single-pass type I integral membrane protein, which binds to pituitary tumor-transforming 1 protein (PTTG1), and facilitates translocation of PTTG1 into the nucleus. Coexpression of this protein and PTTG1 induces transcriptional activation of basic fibroblast growth factor. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Nov 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39550793).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTTG1IP	NM_004339.4	c.419G>C	p.Arg140Pro	missense_variant	Exon 4 of 6	ENST00000330938.8	NP_004330.1
PTTG1IP	NM_001286822.2	c.169-4596G>C		intron_variant	Intron 2 of 2		NP_001273751.1
PTTG1IP	NR_104597.2	n.384G>C		non_coding_transcript_exon_variant	Exon 3 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTTG1IP	ENST00000330938.8	c.419G>C	p.Arg140Pro	missense_variant	Exon 4 of 6	1	NM_004339.4	ENSP00000328325.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461866 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T;.
Eigen	Benign	-0.029
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.40	T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Pathogenic	2.9	M;.
PrimateAI	Benign	0.35	T
PROVEAN	Pathogenic	-4.7	D;D
REVEL	Benign	0.17
Sift	Uncertain	0.013	D;D
Sift4G	Uncertain	0.010	D;D
Polyphen		0.98	D;.
Vest4		0.48
MutPred		0.25		Loss of MoRF binding (P = 0.0047);.;
MVP		0.67
MPC		0.94
ClinPred		0.78	D
GERP RS		1.8
Varity_R		0.58
gMVP		0.34

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-46276138;