12-64043443-C-G

Variant names:

• chr12-64043443-C-G
• rs142477721
• NM_020762.4:c.673-4C>G

Variant summary

Our verdict is Benign. The variant received -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, 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, intron
• Scores: Splicing: ADA: 0.00006069
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.286
• Publications: 0 publications found

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]

SRGAP1 Gene-Disease associations (from GenCC):

• thyroid cancer, nonmedullary, 2

  Inheritance: AD Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000255886 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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. GnomAdExome4 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 GnomAdExome4. There are 290 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High AC in GnomAd4 at 680 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRGAP1	NM_020762.4	c.673-4C>G		splice_region_variant, intron_variant	Intron 5 of 21	ENST00000355086.8	NP_065813.1
SRGAP1	NM_001346201.2	c.673-4C>G		splice_region_variant, intron_variant	Intron 5 of 21		NP_001333130.1
SRGAP1	XM_024449096.2	c.673-4C>G		splice_region_variant, intron_variant	Intron 5 of 13		XP_024304864.1
SRGAP1	XM_024449097.2	c.673-4C>G		splice_region_variant, intron_variant	Intron 5 of 11		XP_024304865.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SRGAP1	ENST00000355086.8	c.673-4C>G		splice_region_variant, intron_variant	Intron 5 of 21	1	NM_020762.4	ENSP00000347198.3

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

GnomAD2 exomes AF: 0.00122 AC: 300 AN: 246358 AF XY: 0.000910

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 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

African (AFR) AF: 0.0174 AC: 578 AN: 33292

American (AMR) AF: 0.000961 AC: 42 AN: 43704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25986

East Asian (EAS) AF: 0.00 AC: 0 AN: 39464

South Asian (SAS) AF: 0.0000236 AC: 2 AN: 84714

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52870

Middle Eastern (MID) AF: 0.00105 AC: 6 AN: 5730

European-Non Finnish (NFE) AF: 0.00000901 AC: 10 AN: 1110228

Other (OTH) AF: 0.00113 AC: 68 AN: 60184

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

African (AFR) AF: 0.0158 AC: 655 AN: 41552

American (AMR) AF: 0.00105 AC: 16 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68022

Other (OTH) AF: 0.00332 AC: 7 AN: 2110

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

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	5.8
DANN	Benign	0.72
PhyloP100		0.29
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs142477721; hg19: chr12-64437223;