rs886041024

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PP2PP3_ModeratePP5

The NM_080675.4(SUN5):c.781G>A(p.Val261Met) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SUN5
NM_080675.4 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 4.04

Publications

4 publications found

Variant links:

Genes affected

SUN5 (HGNC:16252): (Sad1 and UNC84 domain containing 5) The protein encoded by this gene appears to play a role in the meiotic stage of spermatogenesis. The encoded protein localizes to the junction between the sperm head and body and may be involved in nuclear envelope reconstitution and nuclear migration. Mutations in this gene have been implicated in acephalic spermatozoa syndrome. [provided by RefSeq, May 2017]

SUN5 Gene-Disease associations (from GenCC):

spermatogenic failure 16
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

SUN5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM1

In a topological_domain Perinuclear space (size 256) in uniprot entity SUN5_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_080675.4

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 4 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.68847 (below the threshold of 3.09). Trascript score misZ: 0.63256 (below the threshold of 3.09). GenCC associations: The gene is linked to spermatogenic failure 16.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.86

PP5

Variant 20-32985852-C-T is Pathogenic according to our data. Variant chr20-32985852-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 268051.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SUN5	NM_080675.4 link	c.781G>A	p.Val261Met	missense_variant	Exon 11 of 13	ENST00000356173.8	NP_542406.2	Q8TC36A0A384MDU5
SUN5	XM_011528573.2 link	c.850G>A	p.Val284Met	missense_variant	Exon 12 of 14		XP_011526875.1
SUN5	XM_011528574.2 link	c.706G>A	p.Val236Met	missense_variant	Exon 10 of 12		XP_011526876.1	A9Z1W8
SUN5	XM_011528575.2 link	c.511G>A	p.Val171Met	missense_variant	Exon 9 of 11		XP_011526877.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SUN5	ENST00000356173.8 link	c.781G>A	p.Val261Met	missense_variant	Exon 11 of 13	1	NM_080675.4	ENSP00000348496.3		Q8TC36
SUN5	ENST00000375523.7 link	c.706G>A	p.Val236Met	missense_variant	Exon 10 of 12	5		ENSP00000364673.3		A9Z1W8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461824

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111968

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Spermatogenic failure 16

Pathogenic:1

Nov 07, 2016

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.079

.;T

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.87

D;D

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.86

D;D

MetaSVM

Uncertain

0.49

MutationAssessor

Uncertain

2.0

.;M

PhyloP100

4.0

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.3

N;N

REVEL

Uncertain

0.63

Sift

Uncertain

0.0090

D;D

Sift4G

Uncertain

0.0050

D;D

Polyphen

1.0

.;D

Vest4

0.89

MutPred

0.64

.;Gain of sheet (P = 0.0827);

MVP

0.61

MPC

0.68

ClinPred

0.98

GERP RS

5.7

Varity_R

0.31

gMVP

0.60

Mutation Taster

=27/73

disease causing (ClinVar)

(source)

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

Publications

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rs886041024

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over