rs143940810

chr19-36006825-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001039876.3(SYNE4):c.543G>A(p.Arg181=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00614 in 1,604,444 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0095 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0058 (36 hom.)
• Consequence: SYNE4 NM_001039876.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.747

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 19-36006825-C-T is Benign according to our data. Variant chr19-36006825-C-T is described in ClinVar as [Benign]. Clinvar id is 227087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.747 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0095 (1446/152168) while in subpopulation AFR AF= 0.0221 (919/41506). AF 95% confidence interval is 0.021. There are 11 homozygotes in gnomad4. There are 670 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE4	NM_001039876.3	c.543G>A	p.Arg181=	synonymous_variant	4/8	ENST00000324444.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE4	ENST00000324444.9	c.543G>A	p.Arg181=	synonymous_variant	4/8	5	NM_001039876.3	P2

Frequencies

GnomAD3 genomes AF: 0.00950 AC: 1444 AN: 152050 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.0222

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00530

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00602

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.00502 AC: 1125 AN: 224322 Hom.: 3 AF XY: 0.00480 AC XY: 587 AN XY: 122234

Gnomad AFR exome AF: 0.0212

Gnomad AMR exome AF: 0.00449

Gnomad ASJ exome AF: 0.00288

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00214

Gnomad FIN exome AF: 0.000523

Gnomad NFE exome AF: 0.00568

Gnomad OTH exome AF: 0.00492

GnomAD4 exome AF: 0.00579 AC: 8408 AN: 1452276 Hom.: 36 Cov.: 35 AF XY: 0.00576 AC XY: 4155 AN XY: 721734

Gnomad4 AFR exome AF: 0.0220

Gnomad4 AMR exome AF: 0.00427

Gnomad4 ASJ exome AF: 0.00241

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00212

Gnomad4 FIN exome AF: 0.000458

Gnomad4 NFE exome AF: 0.00620

Gnomad4 OTH exome AF: 0.00556

GnomAD4 genome AF: 0.00950 AC: 1446 AN: 152168 Hom.: 11 Cov.: 32 AF XY: 0.00900 AC XY: 670 AN XY: 74406

Gnomad4 AFR AF: 0.0221

Gnomad4 AMR AF: 0.00530

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00602

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00792 Hom.: 3

Bravo AF: 0.0103

Asia WGS AF: 0.000866 AC: 3 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 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 24, 2014

Arg181Arg in exon 4 of SYNE4: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 1.8% (72/4008) of Af rican American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs143940810). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
Cadd	Benign	7.9
Dann	Benign	0.74

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: rs143940810; hg19: chr19-36497727;