7-123954481-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_153189.3(SPAM1):​c.911C>T​(p.Thr304Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,459,442 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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: 0.000014 ( 0 hom. )

Consequence

SPAM1
NM_153189.3 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.968
Variant links:
Genes affected
SPAM1 (HGNC:11217): (sperm adhesion molecule 1) Hyaluronidase degrades hyaluronic acid, a major structural proteoglycan found in extracellular matrices and basement membranes. Six members of the hyaluronidase family are clustered into two tightly linked groups on chromosome 3p21.3 and 7q31.3. This gene was previously referred to as HYAL1 and HYA1 and has since been assigned the official symbol SPAM1; another family member on chromosome 3p21.3 has been assigned HYAL1. This gene encodes a GPI-anchored enzyme located on the human sperm surface and inner acrosomal membrane. This multifunctional protein is a hyaluronidase that enables sperm to penetrate through the hyaluronic acid-rich cumulus cell layer surrounding the oocyte, a receptor that plays a role in hyaluronic acid induced cell signaling, and a receptor that is involved in sperm-zona pellucida adhesion. Abnormal expression of this gene in tumors has implicated this protein in degradation of basement membranes leading to tumor invasion and metastasis. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2010]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.13653669).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SPAM1NM_153189.3 linkc.911C>T p.Thr304Ile missense_variant Exon 3 of 5 ENST00000682466.1 NP_694859.1 P38567-1Q5D1J4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SPAM1ENST00000682466.1 linkc.911C>T p.Thr304Ile missense_variant Exon 3 of 5 NM_153189.3 ENSP00000508393.1 P38567-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000802
AC:
2
AN:
249344
Hom.:
0
AF XY:
0.0000148
AC XY:
2
AN XY:
134914
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000109
Gnomad SAS 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:
0.0000137
AC:
20
AN:
1459442
Hom.:
0
Cov.:
33
AF XY:
0.0000193
AC XY:
14
AN XY:
725696
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000505
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.:
32
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
May 13, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.911C>T (p.T304I) alteration is located in exon 3 (coding exon 1) of the SPAM1 gene. This alteration results from a C to T substitution at nucleotide position 911, causing the threonine (T) at amino acid position 304 to be replaced by an isoleucine (I). 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
0.25
BayesDel_addAF
Benign
-0.49
T
BayesDel_noAF
Benign
-0.71
CADD
Benign
6.9
DANN
Benign
0.38
DEOGEN2
Uncertain
0.48
T;.;T;T;.
Eigen
Benign
-0.93
Eigen_PC
Benign
-0.94
FATHMM_MKL
Benign
0.22
N
LIST_S2
Benign
0.39
.;.;.;T;T
M_CAP
Benign
0.0059
T
MetaRNN
Benign
0.14
T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.99
L;L;L;L;L
PrimateAI
Benign
0.25
T
PROVEAN
Benign
-2.2
N;N;N;N;N
REVEL
Benign
0.088
Sift
Benign
0.53
T;T;T;T;T
Sift4G
Benign
0.21
T;T;T;T;T
Polyphen
0.0050
B;.;B;B;.
Vest4
0.13
MutPred
0.55
Loss of methylation at R305 (P = 0.0817);Loss of methylation at R305 (P = 0.0817);Loss of methylation at R305 (P = 0.0817);Loss of methylation at R305 (P = 0.0817);Loss of methylation at R305 (P = 0.0817);
MVP
0.26
MPC
0.12
ClinPred
0.014
T
GERP RS
0.0013
Varity_R
0.057
gMVP
0.50

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs778138042; hg19: chr7-123594535; API