rs199853331

Positions:

• chr19-36006526-A-G
• chr19-36006526-A-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.764T>C​(p.Ile255Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000458 in 1,608,146 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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 0.00044 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00046 (2 hom.)
• Consequence: SYNE4 NM_001039876.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 2.12

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]

SYNE4 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009841025).
• BP6: Variant 19-36006526-A-G is Benign according to our data. Variant chr19-36006526-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 504863.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=3, Benign=1}.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNE4	NM_001039876.3	c.764T>C	p.Ile255Thr	missense_variant	5/8	ENST00000324444.9	NP_001034965.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYNE4	ENST00000324444.9	c.764T>C	p.Ile255Thr	missense_variant	5/8	5	NM_001039876.3	ENSP00000316130.3

Frequencies

GnomAD3 genomes AF: 0.000447 AC: 68 AN: 152042 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000435

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000677 AC: 158 AN: 233226 Hom.: 0 AF XY: 0.000731 AC XY: 93 AN XY: 127264

Gnomad AFR exome AF: 0.000288

Gnomad AMR exome AF: 0.0000905

Gnomad ASJ exome AF: 0.00718

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00181

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000250

Gnomad OTH exome AF: 0.000525

GnomAD4 exome AF: 0.000460 AC: 670 AN: 1455986 Hom.: 2 Cov.: 35 AF XY: 0.000499 AC XY: 361 AN XY: 723848

Gnomad4 AFR exome AF: 0.000390

Gnomad4 AMR exome AF: 0.000137

Gnomad4 ASJ exome AF: 0.00783

Gnomad4 EAS exome AF: 0.0000507

Gnomad4 SAS exome AF: 0.00199

Gnomad4 FIN exome AF: 0.0000189

Gnomad4 NFE exome AF: 0.000206

Gnomad4 OTH exome AF: 0.000749

GnomAD4 genome AF: 0.000440 AC: 67 AN: 152160 Hom.: 0 Cov.: 32 AF XY: 0.000511 AC XY: 38 AN XY: 74412

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00692

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000711 Hom.: 0

Bravo AF: 0.000385

ESP6500AA AF: 0.000270 AC: 1

ESP6500EA AF: 0.00123 AC: 10

ExAC AF: 0.000572 AC: 69

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 28, 2020	- -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 18, 2021	The c.764T>C (p.I255T) alteration is located in exon 5 (coding exon 5) of the SYNE4 gene. This alteration results from a T to C substitution at nucleotide position 764, causing the isoleucine (I) at amino acid position 255 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 19, 2016	Variant classified as Uncertain Significance - Favor Benign. The p.Ile255Thr var iant in SYNE4 has not been previously reported in individuals with hearing loss, but has been identified in 0.1% (38/50388) of European chromosomes and 0.1% (20 /13834) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, ht tp://exac.broadinstitute.org; dbSNP rs199853331). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. The isoleucine (Ile) at position 255 is not conserved in mammal s or evolutionarily distant species, supporting that a change at this position m ay be tolerated. Additional computational prediction tools do not provide stron g support for or against an impact to the protein. In summary, while the clinica l significance of the p.Ile255Thr variant is uncertain, these data suggest that it is more likely to be benign. -

SYNE4-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 09, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.086	T;T;.
Eigen	Benign	0.018
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.80	.;T;T
M_CAP	Benign	0.0081	T
MetaRNN	Benign	0.0098	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;L;.
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-3.1	D;.;D
REVEL	Benign	0.12
Sift	Uncertain	0.0020	D;.;D
Sift4G	Uncertain	0.015	D;.;D
Polyphen		0.42	B;B;P
Vest4		0.30
MVP		0.51
MPC		0.45
ClinPred		0.034	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.26
gMVP		0.11

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: rs199853331; hg19: chr19-36497428;