12-64043443-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_020762.4(SRGAP1):c.673-4C>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000862 in 1,608,424 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0045 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00048 (6 hom.)
• Consequence: SRGAP1 NM_020762.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00006069
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.286

Genes affected

SRGAP1 (HGNC:17382): (SLIT-ROBO Rho GTPase activating protein 1) The protein encoded by this gene is a GTPase activator, working with the GTPase CDC42 to negatively regulate neuronal migration. The encoded protein interacts with the transmembrane receptor ROBO1 to inactivate CDC42. [provided by RefSeq, Sep 2016]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 12-64043443-C-G is Benign according to our data. Variant chr12-64043443-C-G is described in ClinVar as [Benign]. Clinvar id is 727379.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.000485 (706/1456172) while in subpopulation AFR AF= 0.0174 (578/33292). AF 95% confidence interval is 0.0162. There are 6 homozygotes in gnomad4_exome. There are 290 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SRGAP1	NM_020762.4	c.673-4C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000355086.8
SRGAP1	NM_001346201.2	c.673-4C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
SRGAP1	XM_024449096.2	c.673-4C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
SRGAP1	XM_024449097.2	c.673-4C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SRGAP1	ENST00000355086.8	c.673-4C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_020762.4	A1
	ENST00000535594.1	n.134-503G>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00447 AC: 680 AN: 152134 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0158

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

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: 0.0000294

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00122 AC: 300 AN: 246358 Hom.: 4 AF XY: 0.000910 AC XY: 121 AN XY: 133000

Gnomad AFR exome AF: 0.0165

Gnomad AMR exome AF: 0.000776

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000267

Gnomad OTH exome AF: 0.000664

GnomAD4 exome AF: 0.000485 AC: 706 AN: 1456172 Hom.: 6 Cov.: 30 AF XY: 0.000401 AC XY: 290 AN XY: 724056

Gnomad4 AFR exome AF: 0.0174

Gnomad4 AMR exome AF: 0.000961

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000236

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000901

Gnomad4 OTH exome AF: 0.00113

GnomAD4 genome AF: 0.00447 AC: 680 AN: 152252 Hom.: 4 Cov.: 32 AF XY: 0.00449 AC XY: 334 AN XY: 74438

Gnomad4 AFR AF: 0.0158

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00116 Hom.: 0

Bravo AF: 0.00507

Asia WGS AF: 0.000867 AC: 3 AN: 3476

EpiCase AF: 0.000110

EpiControl AF: 0.0000598

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
Cadd	Benign	5.8
Dann	Benign	0.72

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000061
dbscSNV1_RF	Benign	0.0
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

Publications

LitVar

Other links and lift over

dbSNP: rs142477721; hg19: chr12-64437223;