rs747607749

Variant names:

• chr7-123954483-C-G
• rs747607749
• NM_153189.3:c.913C>G

Your query was ambiguous. Multiple possible variants found:

• chr7-123954483-C-G
• chr7-123954483-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_153189.3(SPAM1):​c.913C>G​(p.Arg305Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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. R305H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPAM1 NM_153189.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.64
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153189.3. 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
	SPAM1	NM_153189.3	MANE Select	c.913C>G	p.Arg305Gly	missense	Exon 3 of 5	NP_694859.1	Q5D1J4
	SPAM1	NM_003117.5		c.913C>G	p.Arg305Gly	missense	Exon 3 of 7	NP_003108.2
	SPAM1	NM_001174044.2		c.913C>G	p.Arg305Gly	missense	Exon 3 of 5	NP_001167515.1	P38567-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPAM1	ENST00000682466.1	MANE Select	c.913C>G	p.Arg305Gly	missense	Exon 3 of 5	ENSP00000508393.1	P38567-1
	SPAM1	ENST00000340011.9	TSL:1	c.913C>G	p.Arg305Gly	missense	Exon 3 of 7	ENSP00000345849.5	P38567-2
	SPAM1	ENST00000439500.5	TSL:1	c.913C>G	p.Arg305Gly	missense	Exon 4 of 6	ENSP00000402123.1	P38567-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.041	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-0.61	T
MutationAssessor	Pathogenic	3.5	M
PhyloP100		2.6
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.71
MutPred		0.82		Loss of methylation at R305 (P = 0.035)
MVP		0.65
MPC		0.62
ClinPred		0.97	D
GERP RS		6.2
Varity_R		0.91
gMVP		0.91
Mutation Taster		=36/64	disease causing

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

Other links and lift over

dbSNP: rs747607749; hg19: chr7-123594537;