rs2285424

Variant names:

• chr19-36008271-C-T
• rs2285424
• NM_001039876.3:c.225G>A
• SYNE4 p.Pro75Pro

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001039876.3(SYNE4):​c.225G>A​(p.Pro75Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.201 in 1,605,578 control chromosomes in the GnomAD database, including 39,697 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P75P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.30 (8857 hom., cov: 31)
  • Exomes 𝑓: 0.19 (30840 hom.)
• Consequence: SYNE4 NM_001039876.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.302
• Publications: 18 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.019).
• BP6: Variant 19-36008271-C-T is Benign according to our data. Variant chr19-36008271-C-T is described in ClinVar as Benign. ClinVar VariationId is 227084.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.302 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.55 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.225G>A	p.Pro75Pro	synonymous	Exon 2 of 8	NP_001034965.1	Q8N205-1
	SYNE4	NM_001297735.3		c.225G>A	p.Pro75Pro	synonymous	Exon 2 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.225G>A	p.Pro75Pro	synonymous	Exon 2 of 8	ENSP00000316130.3	Q8N205-1
	SYNE4	ENST00000340477.9	TSL:1	c.225G>A	p.Pro75Pro	synonymous	Exon 2 of 6	ENSP00000343152.5	Q8N205-2
	SYNE4	ENST00000872005.1		c.225G>A	p.Pro75Pro	synonymous	Exon 2 of 8	ENSP00000542064.1

Frequencies

GnomAD3 genomes AF: 0.295 AC: 44863 AN: 151876 Hom.: 8819 Cov.: 31

Gnomad AFR AF: 0.555

Gnomad AMI AF: 0.279

Gnomad AMR AF: 0.335

Gnomad ASJ AF: 0.0928

Gnomad EAS AF: 0.229

Gnomad SAS AF: 0.165

Gnomad FIN AF: 0.220

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.167

Gnomad OTH AF: 0.256

GnomAD2 exomes AF: 0.228 AC: 54961 AN: 240750 AF XY: 0.212

Gnomad AFR exome AF: 0.559

Gnomad AMR exome AF: 0.399

Gnomad ASJ exome AF: 0.0974

Gnomad EAS exome AF: 0.221

Gnomad FIN exome AF: 0.208

Gnomad NFE exome AF: 0.164

Gnomad OTH exome AF: 0.192

GnomAD4 exome AF: 0.191 AC: 278208 AN: 1453586 Hom.: 30840 Cov.: 32 AF XY: 0.189 AC XY: 136304 AN XY: 722614

African (AFR) AF: 0.569 AC: 18920 AN: 33226

American (AMR) AF: 0.397 AC: 17327 AN: 43600

Ashkenazi Jewish (ASJ) AF: 0.0907 AC: 2316 AN: 25546

East Asian (EAS) AF: 0.229 AC: 9073 AN: 39608

South Asian (SAS) AF: 0.172 AC: 14678 AN: 85092

European-Finnish (FIN) AF: 0.208 AC: 11066 AN: 53098

Middle Eastern (MID) AF: 0.160 AC: 911 AN: 5682

European-Non Finnish (NFE) AF: 0.173 AC: 191959 AN: 1107712

Other (OTH) AF: 0.199 AC: 11958 AN: 60022

GnomAD4 genome AF: 0.296 AC: 44957 AN: 151992 Hom.: 8857 Cov.: 31 AF XY: 0.298 AC XY: 22130 AN XY: 74278

African (AFR) AF: 0.556 AC: 23043 AN: 41448

American (AMR) AF: 0.336 AC: 5130 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0928 AC: 322 AN: 3470

East Asian (EAS) AF: 0.230 AC: 1182 AN: 5148

South Asian (SAS) AF: 0.164 AC: 786 AN: 4806

European-Finnish (FIN) AF: 0.220 AC: 2330 AN: 10580

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.167 AC: 11331 AN: 67948

Other (OTH) AF: 0.256 AC: 538 AN: 2102

Alfa AF: 0.212 Hom.: 6956

Bravo AF: 0.318

Asia WGS AF: 0.217 AC: 755 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Autosomal recessive nonsyndromic hearing loss 76 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	3.2
DANN	Benign	0.54
PhyloP100		-0.30
PromoterAI		0.020	Neutral
Mutation Taster		=100/0	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2285424;

hg19: chr19-36499173;

COSMIC: COSV53324693;

COSMIC: COSV53324693;