Genetic Variant IPP:c.1652-73G>A (chr1-45694588-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000359942.8(IPP):c.1652-73G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.299 in 811,234 control chromosomes in the GnomAD database, including 36,995 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.28 ( 6236 hom., cov: 32)

Exomes 𝑓: 0.30 ( 30759 hom. )

Consequence

IPP
ENST00000359942.8 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.250

Publications

7 publications found

Variant links:

COSMIC-nc: COSV63433594

Genes affected

IPP (HGNC:6108): (intracisternal A particle-promoted polypeptide) The protein encoded by this gene is a member of the kelch family of proteins, which is characterized by a 50 amino acid repeat which interacts with actin. Transcript variants have been described but their full-length nature has not been determined. [provided by RefSeq, Jul 2008]

IPP links:

TMEM69 (HGNC:28035): (transmembrane protein 69) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

TMEM69 links:

ENSG00000230896 (HGNC:):

ENSG00000230896 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.69).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.351 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
IPP	NM_001145349.2 link	c.1652-73G>A	intron_variant	Intron 9 of 9		NP_001138821.1	Q9Y573-2
IPP	XM_047419673.1 link	c.1652-73G>A	intron_variant	Intron 9 of 9		XP_047275629.1
TMEM69	NM_016486.4 link	c.*683C>T	downstream_gene_variant		ENST00000372025.5	NP_057570.2	Q5SWH9

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
IPP	ENST00000359942.8 link	c.1652-73G>A	intron_variant	Intron 9 of 9	1		ENSP00000353024.4	Q9Y573-2
TMEM69	ENST00000372025.5 link	c.*683C>T	downstream_gene_variant		1	NM_016486.4	ENSP00000361095.4	Q5SWH9
ENSG00000230896	ENST00000430643.1 link	n.*96G>A	downstream_gene_variant		2

Frequencies

GnomAD3 genomes

AF:

0.283

AC:

43032

AN:

151888

Hom.:

6216

Cov.:

show subpopulations

Gnomad AFR

AF:

0.241

Gnomad AMI

AF:

0.308

Gnomad AMR

AF:

0.310

Gnomad ASJ

AF:

0.285

Gnomad EAS

AF:

0.346

Gnomad SAS

AF:

0.365

Gnomad FIN

AF:

0.263

Gnomad MID

AF:

0.341

Gnomad NFE

AF:

0.295

Gnomad OTH

AF:

0.302

GnomAD4 exome

AF:

0.303

AC:

199511

AN:

659228

Hom.:

30759

Cov.:

AF XY:

0.305

AC XY:

106834

AN XY:

349810

show subpopulations

African (AFR)

AF:

0.244

AC:

4174

AN:

17094

American (AMR)

AF:

0.325

AC:

10757

AN:

33128

Ashkenazi Jewish (ASJ)

AF:

0.292

AC:

5884

AN:

20162

East Asian (EAS)

AF:

0.316

AC:

10125

AN:

32046

South Asian (SAS)

AF:

0.360

AC:

22732

AN:

63112

European-Finnish (FIN)

AF:

0.271

AC:

13080

AN:

48310

Middle Eastern (MID)

AF:

0.369

AC:

1570

AN:

4250

European-Non Finnish (NFE)

AF:

0.297

AC:

121124

AN:

407612

Other (OTH)

AF:

0.300

AC:

10065

AN:

33514

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

6731

13462

20192

26923

33654

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1834

3668

5502

7336

9170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.283

AC:

43091

AN:

152006

Hom.:

6236

Cov.:

AF XY:

0.284

AC XY:

21086

AN XY:

74274

show subpopulations

African (AFR)

AF:

0.241

AC:

9984

AN:

41470

American (AMR)

AF:

0.311

AC:

4740

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.285

AC:

989

AN:

3470

East Asian (EAS)

AF:

0.346

AC:

1789

AN:

5164

South Asian (SAS)

AF:

0.365

AC:

1758

AN:

4816

European-Finnish (FIN)

AF:

0.263

AC:

2772

AN:

10540

Middle Eastern (MID)

AF:

0.346

AC:

101

AN:

292

European-Non Finnish (NFE)

AF:

0.295

AC:

20023

AN:

67970

Other (OTH)

AF:

0.310

AC:

655

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1573

3146

4720

6293

7866

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

448

896

1344

1792

2240

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.283

Hom.:

1040

Bravo

AF:

0.284

Asia WGS

AF:

0.346

AC:

1205

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

CADD

Benign

7.2

(source)

DANN

Benign

0.56

PhyloP100

0.25

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over