19-36003450-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001039876.3(SYNE4):​c.1102G>A​(p.Val368Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000358 in 1,613,040 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00021 (2 hom.)
• Consequence: SYNE4 NM_001039876.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:4
• Conservation: PhyloP100: -0.179
• 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: 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0069383383).
• BP6: Variant 19-36003450-C-T is Benign according to our data. Variant chr19-36003450-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 235735.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00176 (268/152136) while in subpopulation AFR AF = 0.00607 (252/41490). AF 95% confidence interval is 0.00546. There are 1 homozygotes in GnomAd4. There are 122 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 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.1102G>A	p.Val368Met	missense	Exon 8 of 8	NP_001034965.1	Q8N205-1
	SYNE4	NM_001297735.3		c.763G>A	p.Val255Met	missense	Exon 6 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.1102G>A	p.Val368Met	missense	Exon 8 of 8	ENSP00000316130.3	Q8N205-1
	SYNE4	ENST00000340477.9	TSL:1	c.763G>A	p.Val255Met	missense	Exon 6 of 6	ENSP00000343152.5	Q8N205-2
	SYNE4	ENST00000872005.1		c.1192G>A	p.Val398Met	missense	Exon 8 of 8	ENSP00000542064.1

Frequencies

GnomAD3 genomes AF: 0.00176 AC: 267 AN: 152018 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00607

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000590

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000513 AC: 126 AN: 245828 AF XY: 0.000337

Gnomad AFR exome AF: 0.00700

Gnomad AMR exome AF: 0.000381

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000902

Gnomad OTH exome AF: 0.000335

GnomAD4 exome AF: 0.000212 AC: 310 AN: 1460904 Hom.: 2 Cov.: 31 AF XY: 0.000182 AC XY: 132 AN XY: 726718

African (AFR) AF: 0.00702 AC: 235 AN: 33472

American (AMR) AF: 0.000517 AC: 23 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: 0.0000581 AC: 5 AN: 86094

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

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5766

European-Non Finnish (NFE) AF: 0.00000810 AC: 9 AN: 1111594

Other (OTH) AF: 0.000596 AC: 36 AN: 60364

GnomAD4 genome AF: 0.00176 AC: 268 AN: 152136 Hom.: 1 Cov.: 31 AF XY: 0.00164 AC XY: 122 AN XY: 74360

African (AFR) AF: 0.00607 AC: 252 AN: 41490

American (AMR) AF: 0.000589 AC: 9 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

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

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67998

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.000584 Hom.: 0

Bravo AF: 0.00206

ESP6500AA AF: 0.00493 AC: 20

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000496 AC: 60

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0050	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.24	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.0069	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.18
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.077
Sift	Pathogenic	0.0	D
Polyphen		0.36	B
MVP		0.38
ClinPred		0.070	T
GERP RS		-0.23
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs141202530; hg19: chr19-36494352;