rs79311416

chr19-36006491-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001039876.3(SYNE4):c.799C>T(p.Arg267Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00133 in 1,611,510 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R267Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0068 (14 hom., cov: 32)
  • Exomes 𝑓: 0.00076 (13 hom.)
• Consequence: SYNE4 NM_001039876.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.904

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0033932328).
• BP6: Variant 19-36006491-G-A is Benign according to our data. Variant chr19-36006491-G-A is described in ClinVar as [Benign]. Clinvar id is 227088.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00679 (1034/152172) while in subpopulation AFR AF= 0.0232 (961/41508). AF 95% confidence interval is 0.0219. There are 14 homozygotes in gnomad4. There are 521 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE4	NM_001039876.3	c.799C>T	p.Arg267Trp	missense_variant	5/8	ENST00000324444.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE4	ENST00000324444.9	c.799C>T	p.Arg267Trp	missense_variant	5/8	5	NM_001039876.3	P2

Frequencies

GnomAD3 genomes AF: 0.00677 AC: 1030 AN: 152056 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0231

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00671

GnomAD3 exomes AF: 0.00190 AC: 461 AN: 242636 Hom.: 4 AF XY: 0.00136 AC XY: 179 AN XY: 132102

Gnomad AFR exome AF: 0.0254

Gnomad AMR exome AF: 0.00165

Gnomad ASJ exome AF: 0.000710

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000133

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000100

Gnomad OTH exome AF: 0.00102

GnomAD4 exome AF: 0.000763 AC: 1114 AN: 1459338 Hom.: 13 Cov.: 35 AF XY: 0.000660 AC XY: 479 AN XY: 725792

Gnomad4 AFR exome AF: 0.0264

Gnomad4 AMR exome AF: 0.00164

Gnomad4 ASJ exome AF: 0.000691

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000234

Gnomad4 OTH exome AF: 0.00166

GnomAD4 genome AF: 0.00679 AC: 1034 AN: 152172 Hom.: 14 Cov.: 32 AF XY: 0.00700 AC XY: 521 AN XY: 74418

Gnomad4 AFR AF: 0.0232

Gnomad4 AMR AF: 0.00360

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00664

Alfa AF: 0.00283 Hom.: 1

Bravo AF: 0.00748

ESP6500AA AF: 0.0230 AC: 87

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.00218 AC: 263

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 26, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 24, 2014

Arg267Trp in exon 5 of SYNE4: This variant is not expected to have clinical sign ificance because it has been identified in 2.3% (87/3784) of African American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS; dbSNP rs79311416). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.73
Cadd	Benign	0.10
Dann	Benign	0.64
DEOGEN2	Benign	0.0034	T;T;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.023	N
MetaRNN	Benign	0.0034	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.14	N;N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.10	N;.;N
REVEL	Benign	0.024
Sift	Benign	0.039	D;.;D
Sift4G	Benign	0.14	T;.;T
Polyphen		0.0	B;B;B
Vest4		0.14
MVP		0.11
MPC		0.094
ClinPred		0.0023	T
GERP RS		-5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.031
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

LitVar

Other links and lift over

dbSNP: rs79311416; hg19: chr19-36497393; COSMIC: COSV53324093; COSMIC: COSV53324093;