Genetic Variant NM_001282531.3:c.422_424dupGCA (chr20-50894289-G-GTGC) – ACMG Classification: Benign (-15 pts)

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PM4_SupportingBP6_Very_StrongBS1BS2

The NM_001282531.3(ADNP):c.422_424dupGCA(p.Ser141dup) variant causes a conservative inframe insertion change. The variant allele was found at a frequency of 0.00388 in 1,613,890 control chromosomes in the GnomAD database, including 28 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0025 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0040 ( 27 hom. )

Consequence

ADNP
NM_001282531.3 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 3.66

Publications

0 publications found

Variant links:

Genes affected

ADNP (HGNC:15766): (activity dependent neuroprotector homeobox) Vasoactive intestinal peptide is a neuroprotective factor that has a stimulatory effect on the growth of some tumor cells and an inhibitory effect on others. This gene encodes a protein that is upregulated by vasoactive intestinal peptide and may be involved in its stimulatory effect on certain tumor cells. The encoded protein contains one homeobox and nine zinc finger domains, suggesting that it functions as a transcription factor. This gene is also upregulated in normal proliferative tissues. Finally, the encoded protein may increase the viability of certain cell types through modulation of p53 activity. Alternatively spliced transcript variants encoding the same protein have been described. [provided by RefSeq, Jul 2008]

ADNP Gene-Disease associations (from GenCC):

ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder
Inheritance: AD, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Illumina, Orphanet, G2P, Labcorp Genetics (formerly Invitae), ClinGen

ADNP links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -15 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_001282531.3. Strenght limited to Supporting due to length of the change: 1aa.

BP6

Variant 20-50894289-G-GTGC is Benign according to our data. Variant chr20-50894289-G-GTGC is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 434092.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0025 (381/152314) while in subpopulation NFE AF = 0.00445 (303/68032). AF 95% confidence interval is 0.00404. There are 1 homozygotes in GnomAd4. There are 172 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 381 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001282531.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADNP	NM_001282531.3	MANE Select	c.422_424dupGCA	p.Ser141dup	conservative_inframe_insertion	Exon 6 of 6	NP_001269460.1	Q9H2P0
ADNP	NM_001439000.1		c.638_640dupGCA	p.Ser213dup	conservative_inframe_insertion	Exon 6 of 6	NP_001425929.1
ADNP	NM_001282532.2		c.422_424dupGCA	p.Ser141dup	conservative_inframe_insertion	Exon 4 of 4	NP_001269461.1	Q9H2P0

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADNP	ENST00000621696.5	TSL:5 MANE Select	c.422_424dupGCA	p.Ser141dup	conservative_inframe_insertion	Exon 6 of 6	ENSP00000483881.1	Q9H2P0
ADNP	ENST00000349014.8	TSL:1	c.422_424dupGCA	p.Ser141dup	conservative_inframe_insertion	Exon 4 of 4	ENSP00000342905.3	Q9H2P0
ADNP	ENST00000371602.9	TSL:1	c.422_424dupGCA	p.Ser141dup	conservative_inframe_insertion	Exon 3 of 3	ENSP00000360662.2	Q9H2P0

Frequencies

GnomAD3 genomes

AF:

0.00250

AC:

381

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000772

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00229

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00445

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00230

AC:

577

AN:

251090

AF XY:

0.00218

show subpopulations

Gnomad AFR exome

AF:

0.000923

Gnomad AMR exome

AF:

0.00139

Gnomad ASJ exome

AF:

0.000595

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000324

Gnomad NFE exome

AF:

0.00380

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00402

AC:

5878

AN:

1461576

Hom.:

Cov.:

AF XY:

0.00397

AC XY:

2886

AN XY:

727094

show subpopulations

African (AFR)

AF:

0.000568

AC:

AN:

33440

American (AMR)

AF:

0.00132

AC:

AN:

44660

Ashkenazi Jewish (ASJ)

AF:

0.000191

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00157

AC:

135

AN:

86176

European-Finnish (FIN)

AF:

0.000262

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00486

AC:

5399

AN:

1111910

Other (OTH)

AF:

0.00404

AC:

244

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

356

711

1067

1422

1778

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

216

432

648

864

1080

<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:

0.00250

AC:

381

AN:

152314

Hom.:

Cov.:

AF XY:

0.00231

AC XY:

172

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.000770

AC:

AN:

41564

American (AMR)

AF:

0.00229

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.000414

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00445

AC:

303

AN:

68032

Other (OTH)

AF:

0.00284

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00424

Hom.:

Bravo

AF:

0.00249

Asia WGS

AF:

0.000289

AC:

AN:

3476

EpiCase

AF:

0.00376

EpiControl

AF:

0.00326

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder (2)

ADNP-related disorder (1)

Inborn genetic diseases (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.7

Mutation Taster

=70/30

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over