20-32985809-G-C

Variant names:

• chr20-32985809-G-C
• rs756459525
• NM_080675.4:c.824C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_080675.4(SUN5):​c.824C>G​(p.Thr275Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SUN5 NM_080675.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.83

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SUN5	NM_080675.4	c.824C>G	p.Thr275Arg	missense_variant	Exon 11 of 13	ENST00000356173.8	NP_542406.2
SUN5	XM_011528573.2	c.893C>G	p.Thr298Arg	missense_variant	Exon 12 of 14		XP_011526875.1
SUN5	XM_011528574.2	c.749C>G	p.Thr250Arg	missense_variant	Exon 10 of 12		XP_011526876.1
SUN5	XM_011528575.2	c.554C>G	p.Thr185Arg	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.824C>G	p.Thr275Arg	missense_variant	Exon 11 of 13	1	NM_080675.4	ENSP00000348496.3
SUN5	ENST00000375523.7	c.749C>G	p.Thr250Arg	missense_variant	Exon 10 of 12	5		ENSP00000364673.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461844 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	.;T
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.032	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Pathogenic	3.0	.;M
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-5.5	D;D
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	.;D
Vest4		0.87
MutPred		0.92		.;Loss of catalytic residue at Q277 (P = 0.025);
MVP		0.53
MPC		0.71
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.96
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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

Other links and lift over

dbSNP: rs756459525; hg19: chr20-31573615;