NM_080675.4:c.820C>T

Variant names:

• chr20-32985813-G-A
• rs1210556782
• NM_080675.4:c.820C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 5P and 2B. PM1 PM2 PP2 BP4_Moderate

The NM_080675.4(SUN5):​c.820C>T​(p.Leu274Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SUN5 NM_080675.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.20
• Publications: 0 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 3 ACMG points.

• PM1: In a topological_domain Perinuclear space (size 256) in uniprot entity SUN5_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_080675.4
• 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=0.21167517).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SUN5	NM_080675.4	c.820C>T	p.Leu274Phe	missense_variant	Exon 11 of 13	ENST00000356173.8	NP_542406.2
SUN5	XM_011528573.2	c.889C>T	p.Leu297Phe	missense_variant	Exon 12 of 14		XP_011526875.1
SUN5	XM_011528574.2	c.745C>T	p.Leu249Phe	missense_variant	Exon 10 of 12		XP_011526876.1
SUN5	XM_011528575.2	c.550C>T	p.Leu184Phe	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.820C>T	p.Leu274Phe	missense_variant	Exon 11 of 13	1	NM_080675.4	ENSP00000348496.3
SUN5	ENST00000375523.7	c.745C>T	p.Leu249Phe	missense_variant	Exon 10 of 12	5		ENSP00000364673.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251402 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461846 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 727236

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

American (AMR) AF: 0.0000224 AC: 1 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111982

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 06, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.820C>T (p.L274F) alteration is located in exon 11 (coding exon 11) of the SUN5 gene. This alteration results from a C to T substitution at nucleotide position 820, causing the leucine (L) at amino acid position 274 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.014	.;T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.74	T;T
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.1	.;N
PhyloP100		-1.2
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.44	N;N
REVEL	Benign	0.21
Sift	Benign	0.70	T;T
Sift4G	Benign	0.19	T;T
Polyphen		0.97	.;D
Vest4		0.28
MutPred		0.81		.;Loss of sheet (P = 0.1158);
MVP		0.040
MPC		0.56
ClinPred		0.48	T
GERP RS		-5.3
Varity_R		0.067
gMVP		0.59
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1210556782; hg19: chr20-31573619;