chr12-64062920-TG-GT

Variant names:

• chr12-64062920-TG-GT
• NM_020762.4:c.805_806delTGinsGT

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_020762.4(SRGAP1):​c.805_806delTGinsGT​(p.Cys269Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. The variant is present in control chromosomes in GnomAd MNV project. The variant allele was found at a frequency of 0.0000144 in 4 alleles, including 0 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C269G) has been classified as Uncertain significance.

• Frequency: GnomAD MNV: 𝑓 0.000014 Genomes: not found (cov: 32)
• Consequence: SRGAP1 NM_020762.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.93
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRGAP1	NM_020762.4	c.805_806delTGinsGT	p.Cys269Val	missense_variant		ENST00000355086.8	NP_065813.1
SRGAP1	NM_001346201.2	c.805_806delTGinsGT	p.Cys269Val	missense_variant			NP_001333130.1
SRGAP1	XM_024449096.2	c.805_806delTGinsGT	p.Cys269Val	missense_variant			XP_024304864.1
SRGAP1	XM_024449097.2	c.805_806delTGinsGT	p.Cys269Val	missense_variant			XP_024304865.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SRGAP1	ENST00000355086.8	c.805_806delTGinsGT	p.Cys269Val	missense_variant		1	NM_020762.4	ENSP00000347198.3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

GnomAD MNV AF: 0.0000144 AC: 4 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

SRGAP1-related disorder Uncertain:1

Nov 17, 2022

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SRGAP1 c.805_806delinsGT variant is predicted to result in an in-frame deletion and insertion. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. A different substitution at this codon (p.Cys269Tyr) has been reported in a patient with multicystic dysplastic kidney and was inherited from a mother with a right duplicated kidney (van der Ven AT et al 2018. PubMed ID: 30143558; Hwang DY et al 2015. PubMed ID: 26026792). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.9

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr12-64456700;