chr7-123955040-C-T

Variant names:

• chr7-123955040-C-T
• rs532416858
• NM_153189.3:c.998C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Moderate BP6_Moderate

The NM_153189.3(SPAM1):​c.998C>T​(p.Ala333Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000664 in 1,611,650 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 Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A333S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000054 (0 hom.)
• Consequence: SPAM1 NM_153189.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0890
• Publications: 1 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_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2050305).
• BP6: Variant 7-123955040-C-T is Benign according to our data. Variant chr7-123955040-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2368925.Status of the report is criteria_provided_single_submitter, 1 stars.

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.998C>T	p.Ala333Val	missense	Exon 4 of 5	NP_694859.1	Q5D1J4
	SPAM1	NM_003117.5		c.998C>T	p.Ala333Val	missense	Exon 4 of 7	NP_003108.2
	SPAM1	NM_001174044.2		c.998C>T	p.Ala333Val	missense	Exon 4 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.998C>T	p.Ala333Val	missense	Exon 4 of 5	ENSP00000508393.1	P38567-1
	SPAM1	ENST00000340011.9	TSL:1	c.998C>T	p.Ala333Val	missense	Exon 4 of 7	ENSP00000345849.5	P38567-2
	SPAM1	ENST00000439500.5	TSL:1	c.998C>T	p.Ala333Val	missense	Exon 5 of 6	ENSP00000402123.1	P38567-1

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 151896 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00145

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000736

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000757 AC: 19 AN: 251110 AF XY: 0.0000516

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000377

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000541 AC: 79 AN: 1459636 Hom.: 0 Cov.: 29 AF XY: 0.0000454 AC XY: 33 AN XY: 726174

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000899 AC: 3 AN: 33356

American (AMR) AF: 0.000291 AC: 13 AN: 44620

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26048

East Asian (EAS) AF: 0.00 AC: 0 AN: 39620

South Asian (SAS) AF: 0.00 AC: 0 AN: 86210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.0000531 AC: 59 AN: 1110380

Other (OTH) AF: 0.0000664 AC: 4 AN: 60262

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152014 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74286

African (AFR) AF: 0.0000241 AC: 1 AN: 41512

American (AMR) AF: 0.00145 AC: 22 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000736 AC: 5 AN: 67952

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.0000450 Hom.: 0

Bravo AF: 0.000151

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	8.6
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.50	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.080	N
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.089
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.10
Sift	Benign	0.25	T
Sift4G	Benign	0.27	T
Polyphen		0.72	P
Vest4		0.16
MutPred		0.86		Gain of loop (P = 0.2754)
MVP		0.38
MPC		0.23
ClinPred		0.092	T
GERP RS		-1.4
Varity_R		0.12
gMVP		0.69
Mutation Taster		=94/6	polymorphism

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: rs532416858; hg19: chr7-123595094; COSMIC: COSV56145190; COSMIC: COSV56145190;