20-32997650-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_080675.4(SUN5):c.378G>C(p.Met126Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,613,908 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M126T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

SUN5
NM_080675.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.63

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a topological_domain Perinuclear space (size 256) in uniprot entity SUN5_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_080675.4

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11228943).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SUN5	NM_080675.4 linkuse as main transcript	c.378G>C	p.Met126Ile	missense_variant	6/13	ENST00000356173.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SUN5	ENST00000356173.8 linkuse as main transcript	c.378G>C	p.Met126Ile	missense_variant	6/13	1	NM_080675.4	P2
SUN5	ENST00000375523.7 linkuse as main transcript	c.303G>C	p.Met101Ile	missense_variant	5/12	5		A2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000205

AC:

AN:

1461784

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

727180

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152124

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74300

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 01, 2024

The c.378G>C (p.M126I) alteration is located in exon 6 (coding exon 6) of the SUN5 gene. This alteration results from a G to C substitution at nucleotide position 378, causing the methionine (M) at amino acid position 126 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.60

Cadd

Benign

Dann

Benign

0.93

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.74

T;T

M_CAP

Benign

0.0050

MetaRNN

Benign

0.11

T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.69

N;N

REVEL

Benign

0.028

Sift

Benign

0.040

D;D

Sift4G

Benign

0.34

T;T

Polyphen

0.0080

.;B

Vest4

0.47

MutPred

0.26

.;Gain of methylation at K127 (P = 0.0335);

MVP

0.014

MPC

0.19

ClinPred

0.14

GERP RS

2.9

Varity_R

0.31

gMVP

0.35

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over