NM_080675.4:c.485T>A

Variant names:

• chr20-32995668-A-T
• rs886041023
• NM_080675.4:c.485T>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP2 PP5

The NM_080675.4(SUN5):​c.485T>A​(p.Met162Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SUN5 NM_080675.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.80
• Publications: 4 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 4 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.
• PP5: Variant 20-32995668-A-T is Pathogenic according to our data. Variant chr20-32995668-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 268049.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SUN5	NM_080675.4	c.485T>A	p.Met162Lys	missense_variant	Exon 8 of 13	ENST00000356173.8	NP_542406.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SUN5	ENST00000356173.8	c.485T>A	p.Met162Lys	missense_variant	Exon 8 of 13	1	NM_080675.4	ENSP00000348496.3
SUN5	ENST00000375523.7	c.410T>A	p.Met137Lys	missense_variant	Exon 7 of 12	5		ENSP00000364673.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Spermatogenic failure 16 Pathogenic:1

Nov 07, 2016

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	23
DANN	Benign	0.97
DEOGEN2	Benign	0.029	.;T
Eigen	Benign	0.034
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.63	T;T
M_CAP	Benign	0.0070	T
MetaRNN	Uncertain	0.62	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	.;L
PhyloP100		2.8
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.4	N;N
REVEL	Benign	0.083
Sift	Uncertain	0.012	D;D
Sift4G	Uncertain	0.014	D;D
Polyphen		0.34	.;B
Vest4		0.83
MutPred		0.52		.;Gain of ubiquitination at M162 (P = 0.0042);
MVP		0.048
MPC		0.35
ClinPred		0.92	D
GERP RS		4.9
Varity_R		0.77
gMVP		0.78
Mutation Taster		=34/66	disease causing (ClinVar)

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: rs886041023; hg19: chr20-31583474;