1-32695338-C-T

Variant names:

• chr1-32695338-C-T
• NM_030786.3:c.760G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_030786.3(SYNC):​c.760G>A​(p.Val254Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000643 in 1,399,746 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0000064 (0 hom.)
• Consequence: SYNC NM_030786.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.33

Genes affected

SYNC (HGNC:28897): (syncoilin, intermediate filament protein) This gene encodes a member of the intermediate filament family which contains an N-terminal head domain, followed by a central coiled-coil region and a short C-terminal tail. The protein is highly expressed in skeletal and cardiac muscle. The protein links the dystrophin associated protein complex (DAPC) to desmin filaments in muscle and may have a structural role in striated muscle. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNC	NM_030786.3	c.760G>A	p.Val254Met	missense_variant	Exon 2 of 5	ENST00000409190.8	NP_110413.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNC	ENST00000409190.8	c.760G>A	p.Val254Met	missense_variant	Exon 2 of 5	2	NM_030786.3	ENSP00000386439.3
SYNC	ENST00000373484.4	c.760G>A	p.Val254Met	missense_variant	Exon 2 of 4	2		ENSP00000362583.3
SYNC	ENST00000417633.1	c.*227G>A		downstream_gene_variant		4		ENSP00000401975.1

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome AF: 0.00000643 AC: 9 AN: 1399746 Hom.: 0 Cov.: 98 AF XY: 0.00000724 AC XY: 5 AN XY: 690378

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000556

Gnomad4 OTH exome AF: 0.0000344

GnomAD4 genome Cov.: 28

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 02, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.760G>A (p.V254M) alteration is located in exon 2 (coding exon 2) of the SYNC gene. This alteration results from a G to A substitution at nucleotide position 760, causing the valine (V) at amino acid position 254 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Uncertain	0.069	T
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.058	D
MetaRNN	Uncertain	0.43	T;T
MetaSVM	Uncertain	0.14	D
MutationAssessor	Benign	0.81	L;L
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.92	N;N
REVEL	Uncertain	0.39
Sift	Uncertain	0.022	D;D
Sift4G	Benign	0.13	T;T
Polyphen		1.0	D;D
Vest4		0.45
MutPred		0.45		Gain of MoRF binding (P = 0.102);Gain of MoRF binding (P = 0.102);
MVP		0.69
MPC		1.0
ClinPred		0.88	D
GERP RS		3.5
Varity_R		0.17
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-33160939;