20-32995684-C-G

Position:

• chr20-32995684-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The ENST00000356173.8(SUN5):​c.469G>C​(p.Asp157His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SUN5 ENST00000356173.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.60

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 3 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 ENST00000356173.8
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33216944).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SUN5	NM_080675.4	c.469G>C	p.Asp157His	missense_variant	8/13	ENST00000356173.8	NP_542406.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SUN5	ENST00000356173.8	c.469G>C	p.Asp157His	missense_variant	8/13	1	NM_080675.4	ENSP00000348496	P2
SUN5	ENST00000375523.7	c.394G>C	p.Asp132His	missense_variant	7/12	5		ENSP00000364673	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 15, 2024

The c.469G>C (p.D157H) alteration is located in exon 8 (coding exon 8) of the SUN5 gene. This alteration results from a G to C substitution at nucleotide position 469, causing the aspartic acid (D) at amino acid position 157 to be replaced by a histidine (H). 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	0.33
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.042	.;T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.79	T;T
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.33	T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.9	.;L
MutationTaster	Benign	0.96	D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.62	N;N
REVEL	Benign	0.13
Sift	Uncertain	0.015	D;D
Sift4G	Uncertain	0.031	D;D
Polyphen		1.0	.;D
Vest4		0.43
MutPred		0.30		.;Gain of MoRF binding (P = 0.0407);
MVP		0.31
MPC		0.69
ClinPred		0.96	D
GERP RS		6.0
Varity_R		0.23
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-31583490;