rs141202530

Variant names:

• chr19-36003450-C-A
• rs141202530
• NM_001039876.3:c.1102G>T

Your query was ambiguous. Multiple possible variants found:

• chr19-36003450-C-A
• chr19-36003450-C-G
• chr19-36003450-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001039876.3(SYNE4):​c.1102G>T​(p.Val368Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,904 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V368M) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SYNE4 NM_001039876.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.179
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 76

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24686593).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE4	NM_001039876.3	c.1102G>T	p.Val368Leu	missense_variant	Exon 8 of 8	ENST00000324444.9	NP_001034965.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE4	ENST00000324444.9	c.1102G>T	p.Val368Leu	missense_variant	Exon 8 of 8	5	NM_001039876.3	ENSP00000316130.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460904 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726718

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44472

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86094

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111594

Other (OTH) AF: 0.00 AC: 0 AN: 60364

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	0.0054	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	10
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0050	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.27	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.98	T
PhyloP100		-0.18
PROVEAN	Benign	0.17	N
REVEL	Benign	0.14
Sift	Pathogenic	0.0	D
Polyphen		0.98	D
MutPred		0.072		Loss of relative solvent accessibility (P = 0.0186);
MVP		0.31
ClinPred		0.97	D
GERP RS		-0.23
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.34
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs141202530; hg19: chr19-36494352;