Genetic Variant DAB1:c.1444+8C>G (chr1-57014875-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001365792.1(DAB1):c.1444+8C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000259 in 1,541,990 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

DAB1
NM_001365792.1 splice_region, intron

Scores

Splicing: ADA: 0.00006669

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.255

Publications

0 publications found

Variant links:

Genes affected

DAB1 (HGNC:2661): (DAB adaptor protein 1) The laminar organization of multiple neuronal types in the cerebral cortex is required for normal cognitive function. In mice, the disabled-1 gene plays a central role in brain development, directing the migration of cortical neurons past previously formed neurons to reach their proper layer. This gene is similar to disabled-1, and the protein encoded by this gene is thought to be a signal transducer that interacts with protein kinase pathways to regulate neuronal positioning in the developing brain. [provided by RefSeq, Jan 2017]

DAB1 Gene-Disease associations (from GenCC):

spinocerebellar ataxia type 37
Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

DAB1 links:

LOC112267900 (HGNC:):

LOC112267900 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001365792.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
DAB1	NM_001365792.1	MANE Select	c.1444+8C>G	splice_region intron	N/A	NP_001352721.1	O75553-6
DAB1	NM_001353983.2		c.1444+8C>G	splice_region intron	N/A	NP_001340912.1	O75553-6
DAB1	NM_001353985.2		c.1444+8C>G	splice_region intron	N/A	NP_001340914.1	O75553-6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
DAB1	ENST00000371236.7	TSL:5 MANE Select	c.1444+8C>G	splice_region intron	N/A	ENSP00000360280.1	O75553-6
DAB1	ENST00000420954.6	TSL:1	c.1438+8C>G	splice_region intron	N/A	ENSP00000395296.2	O75553-5
DAB1	ENST00000371231.5	TSL:5	c.1543+8C>G	splice_region intron	N/A	ENSP00000360275.1	O75553-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000151

AC:

AN:

198908

AF XY:

0.00000955

show subpopulations

Gnomad AFR exome

AF:

0.000191

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000144

AC:

AN:

1389742

Hom.:

Cov.:

AF XY:

0.00000293

AC XY:

AN XY:

682298

show subpopulations

African (AFR)

AF:

0.0000637

AC:

AN:

31396

American (AMR)

AF:

0.00

AC:

AN:

36004

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21472

East Asian (EAS)

AF:

0.00

AC:

AN:

38952

South Asian (SAS)

AF:

0.00

AC:

AN:

73880

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50864

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5402

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1074568

Other (OTH)

AF:

0.00

AC:

AN:

57204

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152248

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74442

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000481

AC:

AN:

41544

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2112

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0385499), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

6.0

(source)

DANN

Benign

0.62

PhyloP100

0.26

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000067

dbscSNV1_RF

Benign

0.0

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over