20-32983879-G-C

Variant names:

• chr20-32983879-G-C
• rs765394185
• NM_080675.4:c.1055C>G

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.1055C>G​(p.Thr352Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T352I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SUN5 NM_080675.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.51
• Publications: 1 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, 0.985

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SUN5	NM_080675.4	c.1055C>G	p.Thr352Ser	missense_variant	Exon 13 of 13	ENST00000356173.8	NP_542406.2
SUN5	XM_011528573.2	c.1124C>G	p.Thr375Ser	missense_variant	Exon 14 of 14		XP_011526875.1
SUN5	XM_011528574.2	c.980C>G	p.Thr327Ser	missense_variant	Exon 12 of 12		XP_011526876.1
SUN5	XM_011528575.2	c.785C>G	p.Thr262Ser	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	c.1055C>G	p.Thr352Ser	missense_variant	Exon 13 of 13	1	NM_080675.4	ENSP00000348496.3
SUN5	ENST00000375523.7	c.980C>G	p.Thr327Ser	missense_variant	Exon 12 of 12	5		ENSP00000364673.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	.;T
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.73	T;T
M_CAP	Benign	0.027	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.081	D
MutationAssessor	Uncertain	2.6	.;M
PhyloP100		7.5
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.9	D;D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0060	D;D
Sift4G	Uncertain	0.014	D;D
Polyphen		1.0	.;D
Vest4		0.86
MutPred		0.95		.;Gain of MoRF binding (P = 0.0942);
MVP		0.38
MPC		0.64
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.67
gMVP		0.59
Mutation Taster		=71/29	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

dbSNP: rs765394185; hg19: chr20-31571685;