rs150043310

Positions:

• chr19-36005343-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001039876.3(SYNE4):​c.962G>A​(p.Arg321Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000239 in 1,614,006 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R321W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (6 hom.)
• Consequence: SYNE4 NM_001039876.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -2.21

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008342236).
• BP6: Variant 19-36005343-C-T is Benign according to our data. Variant chr19-36005343-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 504862.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=1}.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE4	NM_001039876.3	c.962G>A	p.Arg321Gln	missense_variant	6/8	ENST00000324444.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE4	ENST00000324444.9	c.962G>A	p.Arg321Gln	missense_variant	6/8	5	NM_001039876.3	P2

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152074 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000341 AC: 85 AN: 249534 Hom.: 2 AF XY: 0.000288 AC XY: 39 AN XY: 135386

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.000695

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00128

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.00264

GnomAD4 exome AF: 0.000241 AC: 352 AN: 1461814 Hom.: 6 Cov.: 31 AF XY: 0.000191 AC XY: 139 AN XY: 727206

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000453

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000132

Gnomad4 OTH exome AF: 0.00230

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152192 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74402

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000333 Hom.: 0

Bravo AF: 0.000283

ExAC AF: 0.000347 AC: 42

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 09, 2022	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 321 of the SYNE4 protein (p.Arg321Gln). This variant is present in population databases (rs150043310, gnomAD 0.1%). 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: 504862). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 13, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 04, 2019	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 12, 2017

p.Arg321Gln in exon 6 of SYNE4: This variant is not expected to have clinical si gnificance due to a lack of conservation across species, including mammals. Of n ote, >10 mammals have a Gln at this position. In addition, computational predict ion tools do not suggest a high likelihood of impact to the protein. This varian t has also been identified in 0.11% (21/18870) of East Asian chromosomes includi ng 2 by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.or g; dbSNP rs150043310). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	1.4
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0023	T;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.017	N
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.0083	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.84	L;L;.
MutationTaster	Benign	0.99	N;N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.080	N;.;N
REVEL	Benign	0.041
Sift	Benign	0.30	T;.;T
Sift4G	Benign	0.40	T;.;T
Polyphen		0.023	B;B;B
Vest4		0.13
MVP		0.23
MPC		0.32
ClinPred		0.052	T
GERP RS		-2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.023
gMVP		0.092

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: rs150043310; hg19: chr19-36496245;