20-32985852-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_080675.4(SUN5):c.781G>A(p.Val261Met) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SUN5 NM_080675.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.04

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 7 ACMG points.

• PM1: In a domain SUN (size 159) in uniprot entity SUN5_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_080675.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.86
• PP5: Variant 20-32985852-C-T is Pathogenic according to our data. Variant chr20-32985852-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 268051.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.781G>A	p.Val261Met	missense_variant	11/13	ENST00000356173.8
SUN5	XM_011528573.2	c.850G>A	p.Val284Met	missense_variant	12/14
SUN5	XM_011528574.2	c.706G>A	p.Val236Met	missense_variant	10/12
SUN5	XM_011528575.2	c.511G>A	p.Val171Met	missense_variant	9/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SUN5	ENST00000356173.8	c.781G>A	p.Val261Met	missense_variant	11/13	1	NM_080675.4	P2
SUN5	ENST00000375523.7	c.706G>A	p.Val236Met	missense_variant	10/12	5		A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461824 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 727228

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Uncertain	0.49	D
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.3	N;N
REVEL	Uncertain	0.63
Sift	Uncertain	0.0090	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	.;D
Vest4		0.89
MutPred		0.64		.;Gain of sheet (P = 0.0827);
MVP		0.61
MPC		0.68
ClinPred		0.98	D
GERP RS		5.7
Varity_R		0.31
gMVP		0.60

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: rs886041024; hg19: chr20-31573658;