rs79311416

Variant names:

• chr19-36006491-G-A
• rs79311416
• NM_001039876.3:c.799C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000324444.9(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. 15/21 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. R267L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0068 (14 hom., cov: 32)
  • Exomes 𝑓: 0.00076 (13 hom.)
• Consequence: SYNE4 ENST00000324444.9 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.904
• Publications: 3 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: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000324444.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE4	NM_001039876.3	MANE Select	c.799C>T	p.Arg267Trp	missense	Exon 5 of 8	NP_001034965.1
	SYNE4	NM_001297735.3		c.460C>T	p.Arg154Trp	missense	Exon 3 of 6	NP_001284664.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE4	ENST00000324444.9	TSL:5 MANE Select	c.799C>T	p.Arg267Trp	missense	Exon 5 of 8	ENSP00000316130.3
	SYNE4	ENST00000340477.9	TSL:1	c.460C>T	p.Arg154Trp	missense	Exon 3 of 6	ENSP00000343152.5
	SYNE4	ENST00000465425.2	TSL:2	n.911C>T		non_coding_transcript_exon	Exon 5 of 7

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

GnomAD2 exomes AF: 0.00190 AC: 461 AN: 242636 AF XY: 0.00136

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 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

African (AFR) AF: 0.0264 AC: 880 AN: 33396

American (AMR) AF: 0.00164 AC: 73 AN: 44386

Ashkenazi Jewish (ASJ) AF: 0.000691 AC: 18 AN: 26048

East Asian (EAS) AF: 0.00 AC: 0 AN: 39598

South Asian (SAS) AF: 0.000128 AC: 11 AN: 85786

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53208

Middle Eastern (MID) AF: 0.00106 AC: 6 AN: 5686

European-Non Finnish (NFE) AF: 0.0000234 AC: 26 AN: 1110954

Other (OTH) AF: 0.00166 AC: 100 AN: 60276

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

African (AFR) AF: 0.0232 AC: 961 AN: 41508

American (AMR) AF: 0.00360 AC: 55 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67970

Other (OTH) AF: 0.00664 AC: 14 AN: 2108

Alfa AF: 0.00327 Hom.: 2

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.14	N
PhyloP100		-0.90
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.024
Sift	Benign	0.039	D
Sift4G	Benign	0.14	T
Polyphen		0.0	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
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: rs79311416; hg19: chr19-36497393; COSMIC: COSV53324093; COSMIC: COSV53324093;