NM_033025.6:c.718G>A

Variant names:

• chr19-15109991-G-A
• rs920926461
• NM_033025.6:c.718G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_033025.6(SYDE1):​c.718G>A​(p.Ala240Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000134 in 1,493,480 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A240S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: SYDE1 NM_033025.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.116
• Publications: 0 publications found

Genes affected

SYDE1 (HGNC:25824): (synapse defective Rho GTPase homolog 1) The protein encoded by this gene is a Rho GTPase-activating protein highly expressed in placenta. The encoded protein is involved in cytoskeletal remodeling and trophoblast cell migration. Decreased expression of this gene has been associated with intrauterine growth restriction (IUGR). [provided by RefSeq, Feb 2017]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.041906863).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033025.6. 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
	SYDE1	NM_033025.6	MANE Select	c.718G>A	p.Ala240Thr	missense	Exon 3 of 8	NP_149014.3
	SYDE1	NM_001300910.2		c.517G>A	p.Ala173Thr	missense	Exon 3 of 8	NP_001287839.1	Q6ZW31-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYDE1	ENST00000342784.7	TSL:2 MANE Select	c.718G>A	p.Ala240Thr	missense	Exon 3 of 8	ENSP00000341489.1	Q6ZW31-1
	SYDE1	ENST00000600440.5	TSL:1	c.517G>A	p.Ala173Thr	missense	Exon 3 of 8	ENSP00000470733.1	Q6ZW31-2
	SYDE1	ENST00000863344.1		c.718G>A	p.Ala240Thr	missense	Exon 3 of 8	ENSP00000533403.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 7.46e-7 AC: 1 AN: 1341358 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 660166

African (AFR) AF: 0.0000366 AC: 1 AN: 27358

American (AMR) AF: 0.00 AC: 0 AN: 29532

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22830

East Asian (EAS) AF: 0.00 AC: 0 AN: 32514

South Asian (SAS) AF: 0.00 AC: 0 AN: 74410

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32710

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4402

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1061768

Other (OTH) AF: 0.00 AC: 0 AN: 55834

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152122 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74314

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000241 AC: 1 AN: 41446

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67974

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	11
DANN	Benign	0.94
DEOGEN2	Benign	0.00085	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.056	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.042	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.71	N
PhyloP100		0.12
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.16	N
REVEL	Benign	0.016
Sift	Benign	0.37	T
Sift4G	Benign	0.26	T
Polyphen		0.0010	B
Vest4		0.024
MutPred		0.29		Gain of phosphorylation at A240 (P = 6e-04)
MVP		0.10
MPC		0.38
ClinPred		0.084	T
GERP RS		-0.35
Varity_R		0.060
gMVP		0.33
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs920926461; hg19: chr19-15220802;