19-36006845-C-G

Variant names:

• chr19-36006845-C-G
• rs77925409
• NM_001039876.3:c.523G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001039876.3(SYNE4):​c.523G>C​(p.Ala175Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00477 in 1,592,706 control chromosomes in the GnomAD database, including 290 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (133 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (157 hom.)
• Consequence: SYNE4 NM_001039876.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.433
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014849007).
• BP6: Variant 19-36006845-C-G is Benign according to our data. Variant chr19-36006845-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 227086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0863 is higher than 0.05.

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.523G>C	p.Ala175Pro	missense	Exon 4 of 8	NP_001034965.1
	SYNE4	NM_001297735.3		c.280-174G>C		intron	N/A	NP_001284664.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE4	ENST00000324444.9	TSL:5 MANE Select	c.523G>C	p.Ala175Pro	missense	Exon 4 of 8	ENSP00000316130.3
	SYNE4	ENST00000340477.9	TSL:1	c.280-174G>C		intron	N/A	ENSP00000343152.5
	SYNE4	ENST00000872005.1		c.523G>C	p.Ala175Pro	missense	Exon 4 of 8	ENSP00000542064.1

Frequencies

GnomAD3 genomes AF: 0.0256 AC: 3889 AN: 152066 Hom.: 133 Cov.: 32

Gnomad AFR AF: 0.0890

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0100

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.0172

GnomAD2 exomes AF: 0.00652 AC: 1327 AN: 203666 AF XY: 0.00509

Gnomad AFR exome AF: 0.0968

Gnomad AMR exome AF: 0.00531

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000176

Gnomad OTH exome AF: 0.00176

GnomAD4 exome AF: 0.00258 AC: 3714 AN: 1440522 Hom.: 157 Cov.: 35 AF XY: 0.00216 AC XY: 1543 AN XY: 714668

African (AFR) AF: 0.0915 AC: 3051 AN: 33334

American (AMR) AF: 0.00573 AC: 225 AN: 39274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25566

East Asian (EAS) AF: 0.00 AC: 0 AN: 38940

South Asian (SAS) AF: 0.0000839 AC: 7 AN: 83478

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51500

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5730

European-Non Finnish (NFE) AF: 0.0000952 AC: 105 AN: 1103026

Other (OTH) AF: 0.00535 AC: 319 AN: 59674

GnomAD4 genome AF: 0.0256 AC: 3889 AN: 152184 Hom.: 133 Cov.: 32 AF XY: 0.0250 AC XY: 1858 AN XY: 74406

African (AFR) AF: 0.0887 AC: 3682 AN: 41504

American (AMR) AF: 0.0100 AC: 153 AN: 15294

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 67980

Other (OTH) AF: 0.0170 AC: 36 AN: 2112

Alfa AF: 0.00427 Hom.: 20

Bravo AF: 0.0291

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0742 AC: 304

ESP6500EA AF: 0.000721 AC: 6

ExAC AF: 0.00698 AC: 834

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.030	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N
PhyloP100		-0.43
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.054
Sift	Benign	0.24	T
Sift4G	Uncertain	0.053	T
Polyphen		0.0010	B
Vest4		0.18
MVP		0.14
MPC		0.50
ClinPred		0.013	T
GERP RS		-1.4
Varity_R		0.20
gMVP		0.62
Mutation Taster		=98/2	polymorphism (auto)

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: rs77925409; hg19: chr19-36497747;