rs797044990

Variant names:

• chr12-64062938-G-A
• rs797044990
• NM_020762.4:c.823G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-64062938-G-A
• chr12-64062938-G-C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP5 BP4 BS2

The NM_020762.4(SRGAP1):​c.823G>A​(p.Ala275Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000753 in 1,460,316 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: SRGAP1 NM_020762.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.82
• Publications: 9 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):

• congenital anomaly of kidney and urinary tract

  Inheritance: AD Classification: MODERATE Submitted by: PanelApp Australia
• thyroid cancer, nonmedullary, 2

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

ENSG00000255886 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PP5: Variant 12-64062938-G-A is Pathogenic according to our data. Variant chr12-64062938-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 208457.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.23666736). . Strength limited to SUPPORTING due to the PP5.
• BS2: High AC in GnomAdExome4 at 11 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020762.4. 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
	SRGAP1	NM_020762.4	MANE Select	c.823G>A	p.Ala275Thr	missense	Exon 7 of 22	NP_065813.1	Q7Z6B7-1
	SRGAP1	NM_001346201.2		c.823G>A	p.Ala275Thr	missense	Exon 7 of 22	NP_001333130.1	Q7Z6B7-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SRGAP1	ENST00000355086.8	TSL:1 MANE Select	c.823G>A	p.Ala275Thr	missense	Exon 7 of 22	ENSP00000347198.3	Q7Z6B7-1
	SRGAP1	ENST00000543397.1	TSL:1	n.2178G>A		non_coding_transcript_exon	Exon 6 of 21
	SRGAP1	ENST00000875666.1		c.760G>A	p.Ala254Thr	missense	Exon 6 of 21	ENSP00000545725.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1460316 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726270

African (AFR) AF: 0.00 AC: 0 AN: 33438

American (AMR) AF: 0.00 AC: 0 AN: 44536

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39598

South Asian (SAS) AF: 0.00 AC: 0 AN: 85942

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000900 AC: 10 AN: 1111222

Other (OTH) AF: 0.0000166 AC: 1 AN: 60328

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Thyroid cancer, nonmedullary, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.065	T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.7	L
PhyloP100		4.8
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.15
Sift	Benign	0.59	T
Sift4G	Benign	0.41	T
Polyphen		0.81	P
Vest4		0.42
MutPred		0.33		Loss of methylation at R279 (P = 0.1972)
MVP		0.46
MPC		0.24
ClinPred		0.59	D
GERP RS		4.8
Varity_R		0.19
gMVP		0.54
Mutation Taster		=10/90	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs797044990; hg19: chr12-64456718;