chr21-44873607-C-T

Variant names:

• chr21-44873607-C-T
• rs370210322
• NM_004339.4:c.10G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_004339.4(PTTG1IP):​c.10G>A​(p.Gly4Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000645 in 1,436,238 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00058 (3 hom.)
• Consequence: PTTG1IP NM_004339.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.927
• Publications: 2 publications found

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

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00754869).
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004339.4. 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
	PTTG1IP	NM_004339.4	MANE Select	c.10G>A	p.Gly4Arg	missense	Exon 1 of 6	NP_004330.1	P53801
	PTTG1IP	NM_001286822.2		c.10G>A	p.Gly4Arg	missense	Exon 1 of 3	NP_001273751.1	B4DPZ0
	PTTG1IP	NR_104597.2		n.84G>A		non_coding_transcript_exon	Exon 1 of 5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PTTG1IP	ENST00000330938.8	TSL:1 MANE Select	c.10G>A	p.Gly4Arg	missense	Exon 1 of 6	ENSP00000328325.3	P53801
	PTTG1IP	ENST00000898882.1		c.10G>A	p.Gly4Arg	missense	Exon 1 of 7	ENSP00000568941.1
	PTTG1IP	ENST00000898881.1		c.10G>A	p.Gly4Arg	missense	Exon 1 of 6	ENSP00000568940.1

Frequencies

GnomAD3 genomes AF: 0.00116 AC: 176 AN: 152114 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00198

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.0192

Gnomad NFE AF: 0.000853

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000857 AC: 53 AN: 61816 AF XY: 0.000768

Gnomad AFR exome AF: 0.00270

Gnomad AMR exome AF: 0.00197

Gnomad ASJ exome AF: 0.000178

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000230

Gnomad NFE exome AF: 0.000861

Gnomad OTH exome AF: 0.00167

GnomAD4 exome AF: 0.000585 AC: 751 AN: 1284008 Hom.: 3 Cov.: 30 AF XY: 0.000555 AC XY: 351 AN XY: 632430

African (AFR) AF: 0.00191 AC: 49 AN: 25664

American (AMR) AF: 0.00195 AC: 41 AN: 20984

Ashkenazi Jewish (ASJ) AF: 0.0000454 AC: 1 AN: 22044

East Asian (EAS) AF: 0.00 AC: 0 AN: 27736

South Asian (SAS) AF: 0.000189 AC: 13 AN: 68668

European-Finnish (FIN) AF: 0.0000943 AC: 3 AN: 31812

Middle Eastern (MID) AF: 0.00506 AC: 27 AN: 5338

European-Non Finnish (NFE) AF: 0.000531 AC: 546 AN: 1028980

Other (OTH) AF: 0.00135 AC: 71 AN: 52782

GnomAD4 genome AF: 0.00116 AC: 176 AN: 152230 Hom.: 0 Cov.: 34 AF XY: 0.00107 AC XY: 80 AN XY: 74430

African (AFR) AF: 0.00197 AC: 82 AN: 41558

American (AMR) AF: 0.00170 AC: 26 AN: 15308

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10612

Middle Eastern (MID) AF: 0.0207 AC: 6 AN: 290

European-Non Finnish (NFE) AF: 0.000853 AC: 58 AN: 67994

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.000723 Hom.: 0

Bravo AF: 0.00137

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00114 AC: 5

ExAC AF: 0.000117 AC: 3

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	15
DANN	Benign	0.90
DEOGEN2	Benign	0.024	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.0075	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.93
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.011
Sift	Benign	0.050	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.0010	B
Vest4		0.12
MutPred		0.30		Gain of MoRF binding (P = 4e-04)
MVP		0.085
MPC		0.31
ClinPred		0.00042	T
GERP RS		-2.4
PromoterAI		-0.0034	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.051
gMVP		0.30
Mutation Taster		=100/0	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: rs370210322; hg19: chr21-46293522;