1-114895489-G-A

Position:

• chr1-114895489-G-A

Variant summary

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

The NM_003176.4(SYCP1):​c.1300G>A​(p.Glu434Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000146 in 1,367,656 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: SYCP1 NM_003176.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.20

Genes affected

SYCP1 (HGNC:11487): (synaptonemal complex protein 1) Enables double-stranded DNA binding activity. Involved in protein homotetramerization. Predicted to be located in synaptonemal complex. Predicted to be active in central element; male germ cell nucleus; and transverse filament. [provided by Alliance of Genome Resources, Apr 2022]

SYCP1 (HGNC:):

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/exons	MANE	Protein	UniProt
SYCP1	NM_003176.4	c.1300G>A	p.Glu434Lys	missense_variant	16/32	ENST00000369522.8	NP_003167.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYCP1	ENST00000369522.8	c.1300G>A	p.Glu434Lys	missense_variant	16/32	1	NM_003176.4	ENSP00000358535.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000146 AC: 2 AN: 1367656 Hom.: 0 Cov.: 26 AF XY: 0.00000147 AC XY: 1 AN XY: 678796

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: 0.00000191

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2023

The c.1300G>A (p.E434K) alteration is located in exon 16 (coding exon 15) of the SYCP1 gene. This alteration results from a G to A substitution at nucleotide position 1300, causing the glutamic acid (E) at amino acid position 434 to be replaced by a lysine (K). 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	Benign	0.10
BayesDel_addAF	Benign	0.0055	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.15	T;.;T;T;T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.84	.;T;T;D;.
M_CAP	Benign	0.010	T
MetaRNN	Uncertain	0.42	T;T;T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.5	M;.;M;.;M
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.8	N;N;.;.;N
REVEL	Benign	0.25
Sift	Uncertain	0.0070	D;D;.;.;D
Sift4G	Benign	0.10	T;D;T;D;T
Polyphen		1.0	D;.;D;.;D
Vest4		0.50
MutPred		0.60		Gain of ubiquitination at E434 (P = 0.0185);Gain of ubiquitination at E434 (P = 0.0185);Gain of ubiquitination at E434 (P = 0.0185);Gain of ubiquitination at E434 (P = 0.0185);Gain of ubiquitination at E434 (P = 0.0185);
MVP		0.37
MPC		0.77
ClinPred		0.82	D
GERP RS		4.9
Varity_R		0.18
gMVP		0.14

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

LitVar

Other links and lift over

dbSNP: rs1204093224; hg19: chr1-115438110; COSMIC: COSV65698648;