19-15109715-G-A

Variant names:

• chr19-15109715-G-A
• rs866999751
• NM_033025.6:c.442G>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.442G>A​(p.Ala148Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000222 in 1,353,774 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: SYDE1 NM_033025.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.294
• Publications: 1 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=0.03620568).

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.442G>A	p.Ala148Thr	missense	Exon 3 of 8	NP_149014.3
	SYDE1	NM_001300910.2		c.241G>A	p.Ala81Thr	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.442G>A	p.Ala148Thr	missense	Exon 3 of 8	ENSP00000341489.1	Q6ZW31-1
	SYDE1	ENST00000600440.5	TSL:1	c.241G>A	p.Ala81Thr	missense	Exon 3 of 8	ENSP00000470733.1	Q6ZW31-2
	SYDE1	ENST00000863344.1		c.442G>A	p.Ala148Thr	missense	Exon 3 of 8	ENSP00000533403.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000222 AC: 3 AN: 1353774 Hom.: 0 Cov.: 31 AF XY: 0.00000452 AC XY: 3 AN XY: 663776

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

African (AFR) AF: 0.00 AC: 0 AN: 29924

American (AMR) AF: 0.00 AC: 0 AN: 33560

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23114

East Asian (EAS) AF: 0.00 AC: 0 AN: 34946

South Asian (SAS) AF: 0.00 AC: 0 AN: 74734

European-Finnish (FIN) AF: 0.0000252 AC: 1 AN: 39638

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4540

European-Non Finnish (NFE) AF: 9.46e-7 AC: 1 AN: 1057372

Other (OTH) AF: 0.0000179 AC: 1 AN: 55946

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000718 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.1
DANN	Benign	0.89
DEOGEN2	Benign	0.0017	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.072	N
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.036	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.92	L
PhyloP100		-0.29
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	0.040	N
REVEL	Benign	0.030
Sift	Benign	0.43	T
Sift4G	Benign	0.63	T
Polyphen		0.0010	B
Vest4		0.033
MutPred		0.17		Gain of glycosylation at A148 (P = 0.0012)
MVP		0.068
MPC		0.38
ClinPred		0.044	T
GERP RS		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.037
gMVP		0.13
Mutation Taster		=99/1	polymorphism

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: rs866999751; hg19: chr19-15220526; COSMIC: COSV61442681; COSMIC: COSV61442681;