Genetic Variant SUN5:p.Leu274Phe (chr20-32985813-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_080675.4(SUN5):c.820C>T(p.Leu274Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SUN5
NM_080675.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.20

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.21167517).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SUN5	NM_080675.4 link	c.820C>T	p.Leu274Phe	missense_variant	Exon 11 of 13	ENST00000356173.8	NP_542406.2	Q8TC36A0A384MDU5
SUN5	XM_011528573.2 link	c.889C>T	p.Leu297Phe	missense_variant	Exon 12 of 14		XP_011526875.1
SUN5	XM_011528574.2 link	c.745C>T	p.Leu249Phe	missense_variant	Exon 10 of 12		XP_011526876.1	A9Z1W8
SUN5	XM_011528575.2 link	c.550C>T	p.Leu184Phe	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.820C>T	p.Leu274Phe	missense_variant	Exon 11 of 13	1	NM_080675.4	ENSP00000348496.3		Q8TC36
SUN5	ENST00000375523.7 link	c.745C>T	p.Leu249Phe	missense_variant	Exon 10 of 12	5		ENSP00000364673.3		A9Z1W8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251402

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135882

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461846

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 06, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.820C>T (p.L274F) alteration is located in exon 11 (coding exon 11) of the SUN5 gene. This alteration results from a C to T substitution at nucleotide position 820, causing the leucine (L) at amino acid position 274 to be replaced by a phenylalanine (F). 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

0.31

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.014

.;T

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.89

FATHMM_MKL

Benign

0.041

LIST_S2

Benign

0.74

T;T

M_CAP

Benign

0.0072

MetaRNN

Benign

0.21

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-1.1

.;N

PrimateAI

Benign

0.42

PROVEAN

Benign

0.44

N;N

REVEL

Benign

0.21

Sift

Benign

0.70

T;T

Sift4G

Benign

0.19

T;T

Polyphen

0.97

.;D

Vest4

0.28

MutPred

0.81

.;Loss of sheet (P = 0.1158);

MVP

0.040

MPC

0.56

ClinPred

0.48

GERP RS

-5.3

Varity_R

0.067

gMVP

0.59

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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