20-32985819-A-G

Variant names:

• chr20-32985819-A-G
• NM_080675.4:c.814T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP2 PP3_Strong

The NM_080675.4(SUN5):​c.814T>C​(p.Ser272Pro) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SUN5 NM_080675.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.23
• 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: Likely_pathogenic. The variant received 9 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, 0.954

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SUN5	NM_080675.4	c.814T>C	p.Ser272Pro	missense_variant	Exon 11 of 13	ENST00000356173.8	NP_542406.2
SUN5	XM_011528573.2	c.883T>C	p.Ser295Pro	missense_variant	Exon 12 of 14		XP_011526875.1
SUN5	XM_011528574.2	c.739T>C	p.Ser247Pro	missense_variant	Exon 10 of 12		XP_011526876.1
SUN5	XM_011528575.2	c.544T>C	p.Ser182Pro	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.814T>C	p.Ser272Pro	missense_variant	Exon 11 of 13	1	NM_080675.4	ENSP00000348496.3
SUN5	ENST00000375523.7	c.739T>C	p.Ser247Pro	missense_variant	Exon 10 of 12	5		ENSP00000364673.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 27, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.814T>C (p.S272P) alteration is located in exon 11 (coding exon 11) of the SUN5 gene. This alteration results from a T to C substitution at nucleotide position 814, causing the serine (S) at amino acid position 272 to be replaced by a proline (P). 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	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	.;T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.66	T;T
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Uncertain	0.18	D
MutationAssessor	Benign	1.8	.;L
PhyloP100		2.2
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.024	D;D
Polyphen		1.0	.;D
Vest4		0.74
MutPred		0.83		.;Loss of sheet (P = 0.0817);
MVP		0.50
MPC		0.74
ClinPred		0.98	D
GERP RS		1.9
Varity_R		0.79
gMVP		0.86
Mutation Taster		=59/41	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: chr20-31573625;