NM_080675.4:c.899G>T

Variant names:

• chr20-32985184-C-A
• rs142172157
• NM_080675.4:c.899G>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_080675.4(SUN5):​c.899G>T​(p.Gly300Val) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G300S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SUN5 NM_080675.4 missense, splice_region
• Scores: Splicing: ADA: 0.5945
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.96
• 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 5 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.876

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.899G>T	p.Gly300Val	missense splice_region	Exon 12 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.899G>T	p.Gly300Val	missense splice_region	Exon 12 of 13	ENSP00000348496.3	Q8TC36
	SUN5	ENST00000375523.7	TSL:5	c.824G>T	p.Gly275Val	missense splice_region	Exon 11 of 12	ENSP00000364673.3	A9Z1W8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.81	T
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		4.0
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-7.7	D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.54		Loss of disorder (P = 0.0825)
MVP		0.58
MPC		0.76
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.77
gMVP		0.80
Mutation Taster		=58/42	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.59
dbscSNV1_RF	Benign	0.57
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: rs142172157; hg19: chr20-31572990;