rs760765349

Variant names:

• chr20-32989690-C-A
• rs760765349
• NM_080675.4:c.543G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_080675.4(SUN5):​c.543G>T​(p.Met181Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,886 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: SUN5 NM_080675.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.353
• 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: Uncertain_significance. The variant received 1 ACMG points.

• 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=0.08446506).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080675.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SUN5	NM_080675.4	MANE Select	c.543G>T	p.Met181Ile	missense	Exon 9 of 13	NP_542406.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SUN5	ENST00000356173.8	TSL:1 MANE Select	c.543G>T	p.Met181Ile	missense	Exon 9 of 13	ENSP00000348496.3	Q8TC36
	SUN5	ENST00000375523.7	TSL:5	c.468G>T	p.Met156Ile	missense	Exon 8 of 12	ENSP00000364673.3	A9Z1W8

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152048 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251406 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461838 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727218

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111984

Other (OTH) AF: 0.0000662 AC: 4 AN: 60392

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152048 Hom.: 1 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74284

African (AFR) AF: 0.0000242 AC: 1 AN: 41378

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	19
DANN	Benign	0.81
DEOGEN2	Benign	0.0027	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.084	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.35
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.80	N
REVEL	Benign	0.067
Sift	Benign	0.64	T
Sift4G	Benign	0.29	T
Polyphen		0.0	B
Vest4		0.24
MutPred		0.42		Loss of catalytic residue at M181 (P = 0.0172)
MVP		0.030
MPC		0.18
ClinPred		0.24	T
GERP RS		4.8
Varity_R		0.30
gMVP		0.45
Mutation Taster		=93/7	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: rs760765349; hg19: chr20-31577496;