NM_001365792.1:c.1660G>T

Variant names:

• chr1-57010703-C-A
• rs114941053
• NM_001365792.1:c.1660G>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001365792.1(DAB1):​c.1660G>T​(p.Gly554Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000798 in 1,571,932 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G554S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0043 (6 hom., cov: 33)
  • Exomes 𝑓: 0.00042 (3 hom.)
• Consequence: DAB1 NM_001365792.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.12
• Publications: 5 publications found

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)

LOC112267900 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008557349).
• BP6: Variant 1-57010703-C-A is Benign according to our data. Variant chr1-57010703-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 786991.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 655 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DAB1	NM_001365792.1	MANE Select	c.1660G>T	p.Gly554Cys	missense	Exon 14 of 15	NP_001352721.1	O75553-6
	DAB1	NM_001353983.2		c.1660G>T	p.Gly554Cys	missense	Exon 14 of 15	NP_001340912.1	O75553-6
	DAB1	NM_001353985.2		c.1660G>T	p.Gly554Cys	missense	Exon 14 of 15	NP_001340914.1	O75553-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DAB1	ENST00000371236.7	TSL:5 MANE Select	c.1660G>T	p.Gly554Cys	missense	Exon 14 of 15	ENSP00000360280.1	O75553-6
	DAB1	ENST00000420954.6	TSL:1	c.1654G>T	p.Gly552Cys	missense	Exon 13 of 14	ENSP00000395296.2	O75553-5
	DAB1	ENST00000371231.5	TSL:5	c.1759G>T	p.Gly587Cys	missense	Exon 15 of 15	ENSP00000360275.1	O75553-1

Frequencies

GnomAD3 genomes AF: 0.00429 AC: 653 AN: 152134 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.0147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00112 AC: 263 AN: 235822 AF XY: 0.000838

Gnomad AFR exome AF: 0.0136

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.000437

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000924

Gnomad OTH exome AF: 0.000355

GnomAD4 exome AF: 0.000423 AC: 600 AN: 1419680 Hom.: 3 Cov.: 29 AF XY: 0.000386 AC XY: 271 AN XY: 702820

African (AFR) AF: 0.0127 AC: 408 AN: 32000

American (AMR) AF: 0.00130 AC: 53 AN: 40758

Ashkenazi Jewish (ASJ) AF: 0.000605 AC: 15 AN: 24808

East Asian (EAS) AF: 0.00 AC: 0 AN: 38590

South Asian (SAS) AF: 0.0000373 AC: 3 AN: 80372

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52488

Middle Eastern (MID) AF: 0.000540 AC: 3 AN: 5558

European-Non Finnish (NFE) AF: 0.0000506 AC: 55 AN: 1086860

Other (OTH) AF: 0.00108 AC: 63 AN: 58246

GnomAD4 genome AF: 0.00430 AC: 655 AN: 152252 Hom.: 6 Cov.: 33 AF XY: 0.00416 AC XY: 310 AN XY: 74440

African (AFR) AF: 0.0147 AC: 610 AN: 41554

American (AMR) AF: 0.00190 AC: 29 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68006

Other (OTH) AF: 0.00473 AC: 10 AN: 2112

Alfa AF: 0.00140 Hom.: 1

Bravo AF: 0.00471

ESP6500AA AF: 0.0145 AC: 64

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00132 AC: 160

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.22
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0086	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	0.81	L
PhyloP100		4.1
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.19
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.010	D
Polyphen		0.99	D
Vest4		0.49
MVP		0.64
MPC		1.0
ClinPred		0.045	T
GERP RS		2.1
Varity_R		0.24
gMVP		0.30
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs114941053; hg19: chr1-57476376; COSMIC: COSV104680207; COSMIC: COSV104680207;