rs147433902

Variant names:

• chr19-36006485-G-A
• rs147433902
• NM_001039876.3:c.805C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001039876.3(SYNE4):​c.805C>T​(p.Leu269Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00565 in 1,612,300 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0050 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0057 (40 hom.)
• Consequence: SYNE4 NM_001039876.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.04
• Publications: 1 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: Labcorp Genetics (formerly Invitae), PanelApp Australia
• 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 19-36006485-G-A is Benign according to our data. Variant chr19-36006485-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 227089.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.04 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00501 (762/152236) while in subpopulation AMR AF = 0.012 (184/15286). AF 95% confidence interval is 0.0106. There are 5 homozygotes in GnomAd4. There are 356 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001039876.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE4	NM_001039876.3	MANE Select	c.805C>T	p.Leu269Leu	synonymous	Exon 5 of 8	NP_001034965.1	Q8N205-1
	SYNE4	NM_001297735.3		c.466C>T	p.Leu156Leu	synonymous	Exon 3 of 6	NP_001284664.1	Q8N205-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE4	ENST00000324444.9	TSL:5 MANE Select	c.805C>T	p.Leu269Leu	synonymous	Exon 5 of 8	ENSP00000316130.3	Q8N205-1
	SYNE4	ENST00000340477.9	TSL:1	c.466C>T	p.Leu156Leu	synonymous	Exon 3 of 6	ENSP00000343152.5	Q8N205-2
	SYNE4	ENST00000872005.1		c.805C>T	p.Leu269Leu	synonymous	Exon 5 of 8	ENSP00000542064.1

Frequencies

GnomAD3 genomes AF: 0.00502 AC: 764 AN: 152118 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000941

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0121

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00635

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.00528 AC: 1293 AN: 244674 AF XY: 0.00545

Gnomad AFR exome AF: 0.00106

Gnomad AMR exome AF: 0.00753

Gnomad ASJ exome AF: 0.0133

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00114

Gnomad NFE exome AF: 0.00690

Gnomad OTH exome AF: 0.0109

GnomAD4 exome AF: 0.00572 AC: 8353 AN: 1460064 Hom.: 40 Cov.: 35 AF XY: 0.00568 AC XY: 4126 AN XY: 726192

African (AFR) AF: 0.00108 AC: 36 AN: 33428

American (AMR) AF: 0.00831 AC: 370 AN: 44500

Ashkenazi Jewish (ASJ) AF: 0.0132 AC: 345 AN: 26080

East Asian (EAS) AF: 0.00 AC: 0 AN: 39654

South Asian (SAS) AF: 0.00111 AC: 95 AN: 85906

European-Finnish (FIN) AF: 0.00150 AC: 80 AN: 53282

Middle Eastern (MID) AF: 0.0222 AC: 125 AN: 5636

European-Non Finnish (NFE) AF: 0.00620 AC: 6895 AN: 1111264

Other (OTH) AF: 0.00675 AC: 407 AN: 60314

GnomAD4 genome AF: 0.00501 AC: 762 AN: 152236 Hom.: 5 Cov.: 32 AF XY: 0.00478 AC XY: 356 AN XY: 74424

African (AFR) AF: 0.000939 AC: 39 AN: 41554

American (AMR) AF: 0.0120 AC: 184 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0190 AC: 66 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4826

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10622

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00635 AC: 432 AN: 67996

Other (OTH) AF: 0.0133 AC: 28 AN: 2108

Alfa AF: 0.00628 Hom.: 3

Bravo AF: 0.00621

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	SYNE4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.74
DANN	Benign	0.63
PhyloP100		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs147433902; hg19: chr19-36497387;