rs200994810

chr19-36007231-T-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_001039876.3(SYNE4):c.317A>C(p.Gln106Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000975 in 1,594,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00070 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (0 hom.)
• Consequence: SYNE4 NM_001039876.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.169

Genes affected

SYNE4 (HGNC:26703): (spectrin repeat containing nuclear envelope family member 4) This gene is a member of the nesprin family of genes, that encode KASH (Klarsicht, Anc-1, Syne Homology) domain-containing proteins. In addition to the KASH domain, this protein also contains a coiled-coil and leucine zipper region, a spectrin repeat, and a kinesin-1 binding region. This protein localizes to the outer nuclear membrane, and is part of the linker of nucleoskeleton and cytoskeleton (LINC) complex in the nuclear envelope. LINC complexes are formed by SUN (Sad1, UNC-84)-KASH pairs, and are thought to mechanically couple nuclear components to the cytoskeleton. Mutations in this gene have been associated with progressive high-frequency hearing loss. The absence of this protein in mice also caused hearing loss, and changes in hair cell morphology in the ears. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2015]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.023179948).
• BP6: Variant 19-36007231-T-G is Benign according to our data. Variant chr19-36007231-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 229283.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE4	NM_001039876.3	c.317A>C	p.Gln106Pro	missense_variant	3/8	ENST00000324444.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE4	ENST00000324444.9	c.317A>C	p.Gln106Pro	missense_variant	3/8	5	NM_001039876.3	P2

Frequencies

GnomAD3 genomes AF: 0.000703 AC: 107 AN: 152256 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00132

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000630 AC: 135 AN: 214194 Hom.: 0 AF XY: 0.000654 AC XY: 76 AN XY: 116132

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000196

Gnomad ASJ exome AF: 0.000109

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000150

Gnomad FIN exome AF: 0.0000544

Gnomad NFE exome AF: 0.00127

Gnomad OTH exome AF: 0.000189

GnomAD4 exome AF: 0.00100 AC: 1449 AN: 1442366 Hom.: 0 Cov.: 35 AF XY: 0.000967 AC XY: 692 AN XY: 715502

Gnomad4 AFR exome AF: 0.0000902

Gnomad4 AMR exome AF: 0.0000966

Gnomad4 ASJ exome AF: 0.0000783

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000181

Gnomad4 FIN exome AF: 0.000136

Gnomad4 NFE exome AF: 0.00124

Gnomad4 OTH exome AF: 0.000620

GnomAD4 genome AF: 0.000696 AC: 106 AN: 152374 Hom.: 0 Cov.: 32 AF XY: 0.000711 AC XY: 53 AN XY: 74508

Gnomad4 AFR AF: 0.000240

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00132

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00133 Hom.: 0

Bravo AF: 0.000657

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000965 AC: 8

ExAC AF: 0.000457 AC: 55

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 12, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 05, 2019	proposed classification - variant undergoing re-assessment, contact laboratory -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 18, 2022	This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 106 of the SYNE4 protein (p.Gln106Pro). This variant is present in population databases (rs200994810, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with SYNE4-related conditions. ClinVar contains an entry for this variant (Variation ID: 229283). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SYNE4 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.096	T;T;T
Eigen	Benign	0.13
Eigen_PC	Benign	0.031
FATHMM_MKL	Benign	0.47	N
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.023	T;T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	2.0	M;M;.
MutationTaster	Benign	1.0	D;N
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.3	D;.;D
REVEL	Benign	0.23
Sift	Uncertain	0.0050	D;.;D
Sift4G	Uncertain	0.0070	D;.;.
Polyphen		0.94	P;P;D
Vest4		0.52
MVP		0.53
MPC		0.29
ClinPred		0.088	T
GERP RS		1.9
Varity_R		0.57
gMVP		0.80

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: rs200994810; hg19: chr19-36498133;