20-32995668-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 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

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a topological_domain Perinuclear space (size 256) in uniprot entity SUN5_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_080675.4
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 20-32995668-A-T is Pathogenic according to our data. Variant chr20-32995668-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 268049.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SUN5	NM_080675.4	c.485T>A	p.Met162Lys	missense_variant	8/13	ENST00000356173.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SUN5	ENST00000356173.8	c.485T>A	p.Met162Lys	missense_variant	8/13	1	NM_080675.4	P2
SUN5	ENST00000375523.7	c.410T>A	p.Met137Lys	missense_variant	7/12	5		A2

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 07, 2016

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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
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
MutationTaster	Benign	0.78	N;N
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs886041023; hg19: chr20-31583474;