chr19-36008544-C-T

Variant names:

• chr19-36008544-C-T
• rs376639796
• NM_001039876.3:c.128+10G>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.128+10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000392 in 1,613,452 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00038 (2 hom.)
• Consequence: SYNE4 NM_001039876.3 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.759

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]

ENSG00000248101 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 19-36008544-C-T is Benign according to our data. Variant chr19-36008544-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 504815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-36008544-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000382 (558/1461106) while in subpopulation MID AF= 0.00625 (33/5280). AF 95% confidence interval is 0.00457. There are 2 homozygotes in gnomad4_exome. There are 261 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE4	NM_001039876.3	c.128+10G>A		intron_variant	Intron 1 of 7	ENST00000324444.9	NP_001034965.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE4	ENST00000324444.9	c.128+10G>A		intron_variant	Intron 1 of 7	5	NM_001039876.3	ENSP00000316130.3

Frequencies

GnomAD3 genomes AF: 0.000493 AC: 75 AN: 152228 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000535 AC: 133 AN: 248806 Hom.: 1 AF XY: 0.000563 AC XY: 76 AN XY: 135018

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.000797

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000232

Gnomad NFE exome AF: 0.000666

Gnomad OTH exome AF: 0.000827

GnomAD4 exome AF: 0.000382 AC: 558 AN: 1461106 Hom.: 2 Cov.: 31 AF XY: 0.000359 AC XY: 261 AN XY: 726876

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.00101

Gnomad4 ASJ exome AF: 0.00176

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.000281

Gnomad4 NFE exome AF: 0.000315

Gnomad4 OTH exome AF: 0.000945

GnomAD4 genome AF: 0.000492 AC: 75 AN: 152346 Hom.: 0 Cov.: 32 AF XY: 0.000456 AC XY: 34 AN XY: 74498

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000603

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000430 Hom.: 0

Bravo AF: 0.000627

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 26, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Jun 08, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.128+10G>A in intron 1 of SYNE4: This variant is not expected to have clinical significance because it is not located within the conserved splice consensus seq uence. It has been identified in several populations including 34/34418 Latino c hromosomes and 82/126288 European chromosomes including 1 homozygote by the Geno me Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs37663 9796). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	9.9
DANN	Benign	0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs376639796; hg19: chr19-36499446;