Genetic Variant SUN5:p.Pro374Ser (chr20-32983814-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_080675.4(SUN5):c.1120C>T(p.Pro374Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000533 in 1,557,810 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 (★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000049 ( 0 hom. )

Consequence

SUN5
NM_080675.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.369

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.058188677).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SUN5	NM_080675.4 link	c.1120C>T	p.Pro374Ser	missense_variant	Exon 13 of 13	ENST00000356173.8	NP_542406.2	Q8TC36A0A384MDU5
SUN5	XM_011528573.2 link	c.1189C>T	p.Pro397Ser	missense_variant	Exon 14 of 14		XP_011526875.1
SUN5	XM_011528574.2 link	c.1045C>T	p.Pro349Ser	missense_variant	Exon 12 of 12		XP_011526876.1	A9Z1W8
SUN5	XM_011528575.2 link	c.850C>T	p.Pro284Ser	missense_variant	Exon 11 of 11		XP_011526877.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SUN5	ENST00000356173.8 link	c.1120C>T	p.Pro374Ser	missense_variant	Exon 13 of 13	1	NM_080675.4	ENSP00000348496.3		Q8TC36
SUN5	ENST00000375523.7 link	c.1045C>T	p.Pro349Ser	missense_variant	Exon 12 of 12	5		ENSP00000364673.3		A9Z1W8

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000592

AC:

AN:

219536

Hom.:

AF XY:

0.0000671

AC XY:

AN XY:

119198

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000115

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000406

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000870

Gnomad OTH exome

AF:

0.000394

GnomAD4 exome

AF:

0.0000491

AC:

AN:

1405590

Hom.:

Cov.:

AF XY:

0.0000547

AC XY:

AN XY:

695074

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000267

Gnomad4 ASJ exome

AF:

0.000243

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000393

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000489

Gnomad4 OTH exome

AF:

0.0000517

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000827

Hom.:

Bravo

AF:

0.0000756

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1120C>T (p.P374S) alteration is located in exon 13 (coding exon 13) of the SUN5 gene. This alteration results from a C to T substitution at nucleotide position 1120, causing the proline (P) at amino acid position 374 to be replaced by a serine (S). 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

0.073

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.64

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.0015

.;T

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.55

T;T

M_CAP

Benign

0.0049

MetaRNN

Benign

0.058

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

.;N

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.33

N;N

REVEL

Benign

0.047

Sift

Uncertain

0.013

D;D

Sift4G

Benign

0.20

T;T

Polyphen

0.041

.;B

Vest4

0.25

MVP

0.055

MPC

0.16

ClinPred

0.050

GERP RS

3.2

Varity_R

0.065

gMVP

0.37

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

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