20-32985789-T-A

Variant names:

• chr20-32985789-T-A
• NM_080675.4:c.844A>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 5P and 2B. PM1 PM2 PP2 BP4_Moderate

The NM_080675.4(SUN5):​c.844A>T​(p.Thr282Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SUN5 NM_080675.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.29
• Publications: 0 publications found

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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.16933668).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SUN5	NM_080675.4	c.844A>T	p.Thr282Ser	missense_variant	Exon 11 of 13	ENST00000356173.8	NP_542406.2
SUN5	XM_011528573.2	c.913A>T	p.Thr305Ser	missense_variant	Exon 12 of 14		XP_011526875.1
SUN5	XM_011528574.2	c.769A>T	p.Thr257Ser	missense_variant	Exon 10 of 12		XP_011526876.1
SUN5	XM_011528575.2	c.574A>T	p.Thr192Ser	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	c.844A>T	p.Thr282Ser	missense_variant	Exon 11 of 13	1	NM_080675.4	ENSP00000348496.3
SUN5	ENST00000375523.7	c.769A>T	p.Thr257Ser	missense_variant	Exon 10 of 12	5		ENSP00000364673.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 07, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.844A>T (p.T282S) alteration is located in exon 11 (coding exon 11) of the SUN5 gene. This alteration results from a A to T substitution at nucleotide position 844, causing the threonine (T) at amino acid position 282 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	0.13
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.014	.;T
Eigen	Benign	0.0043
Eigen_PC	Benign	0.085
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.49	T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.065	.;N
PhyloP100		1.3
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.13
Sift	Benign	0.49	T;T
Sift4G	Benign	0.59	T;T
Polyphen		1.0	.;D
Vest4		0.31
MutPred		0.31		.;Gain of disorder (P = 0.0287);
MVP		0.11
MPC		0.20
ClinPred		0.79	D
GERP RS		4.6
Varity_R		0.20
gMVP		0.28
Mutation Taster		=75/25	polymorphism

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

Other links and lift over

hg19: chr20-31573595;