NM_152291.3:c.-15-1G>A

Variant names:

• chr4-70474006-G-A
• rs2306949
• NM_152291.3:c.-15-1G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PVS1_Moderate BA1

The NM_152291.3(MUC7):​c.-15-1G>A variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.164 in 1,601,096 control chromosomes in the GnomAD database, including 23,406 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.18 (2913 hom., cov: 31)
  • Exomes 𝑓: 0.16 (20493 hom.)
• Consequence: MUC7 NM_152291.3 splice_acceptor, intron
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.187
• Publications: 17 publications found

Genes affected

MUC7 (HGNC:7518): (mucin 7, secreted) This gene encodes a small salivary mucin, which is thought to play a role in facilitating the clearance of bacteria in the oral cavity and to aid in mastication, speech, and swallowing. The central domain of this glycoprotein contains tandem repeats, each composed of 23 amino acids. This antimicrobial protein has antibacterial and antifungal activity. The most common allele contains 6 repeats, and some alleles may be associated with susceptibility to asthma. Alternatively spliced transcript variants with different 5' UTR, but encoding the same protein, have been found for this gene. [provided by RefSeq, Oct 2014]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.06084656 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.3, offset of 1, new splice context is: acatttctgcttttcccaAGaga. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.268 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUC7	NM_152291.3	c.-15-1G>A		splice_acceptor_variant, intron_variant	Intron 1 of 2	ENST00000304887.6	NP_689504.2
MUC7	NM_001145006.2	c.-15-1G>A		splice_acceptor_variant, intron_variant	Intron 2 of 3		NP_001138478.1
MUC7	NM_001145007.2	c.-15-1G>A		splice_acceptor_variant, intron_variant	Intron 2 of 3		NP_001138479.1
MUC7	XM_047415723.1	c.-15-1G>A		splice_acceptor_variant, intron_variant	Intron 2 of 3		XP_047271679.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUC7	ENST00000304887.6	c.-15-1G>A		splice_acceptor_variant, intron_variant	Intron 1 of 2	1	NM_152291.3	ENSP00000302021.5

Frequencies

GnomAD3 genomes AF: 0.184 AC: 27962 AN: 151604 Hom.: 2907 Cov.: 31

Gnomad AFR AF: 0.272

Gnomad AMI AF: 0.169

Gnomad AMR AF: 0.115

Gnomad ASJ AF: 0.0827

Gnomad EAS AF: 0.185

Gnomad SAS AF: 0.222

Gnomad FIN AF: 0.111

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.162

Gnomad OTH AF: 0.157

GnomAD2 exomes AF: 0.162 AC: 40466 AN: 250348 AF XY: 0.162

Gnomad AFR exome AF: 0.271

Gnomad AMR exome AF: 0.112

Gnomad ASJ exome AF: 0.0946

Gnomad EAS exome AF: 0.175

Gnomad FIN exome AF: 0.119

Gnomad NFE exome AF: 0.159

Gnomad OTH exome AF: 0.145

GnomAD4 exome AF: 0.162 AC: 234453 AN: 1449374 Hom.: 20493 Cov.: 29 AF XY: 0.162 AC XY: 116953 AN XY: 721482

African (AFR) AF: 0.277 AC: 9159 AN: 33116

American (AMR) AF: 0.115 AC: 5138 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.0950 AC: 2476 AN: 26054

East Asian (EAS) AF: 0.146 AC: 5778 AN: 39558

South Asian (SAS) AF: 0.210 AC: 17993 AN: 85612

European-Finnish (FIN) AF: 0.125 AC: 6625 AN: 53142

Middle Eastern (MID) AF: 0.105 AC: 604 AN: 5732

European-Non Finnish (NFE) AF: 0.161 AC: 176937 AN: 1101546

Other (OTH) AF: 0.162 AC: 9743 AN: 59974

GnomAD4 genome AF: 0.184 AC: 27985 AN: 151722 Hom.: 2913 Cov.: 31 AF XY: 0.181 AC XY: 13422 AN XY: 74130

African (AFR) AF: 0.272 AC: 11229 AN: 41294

American (AMR) AF: 0.115 AC: 1754 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.0827 AC: 286 AN: 3458

East Asian (EAS) AF: 0.185 AC: 954 AN: 5156

South Asian (SAS) AF: 0.222 AC: 1067 AN: 4796

European-Finnish (FIN) AF: 0.111 AC: 1166 AN: 10534

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.162 AC: 11012 AN: 67916

Other (OTH) AF: 0.156 AC: 329 AN: 2108

Alfa AF: 0.169 Hom.: 5878

Bravo AF: 0.186

Asia WGS AF: 0.186 AC: 650 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	23
DANN	Benign	0.93
PhyloP100		0.19
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.87
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.86		Position offset: 2
DS_AL_spliceai		1.0		Position offset: 1

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

Other links and lift over

dbSNP: rs2306949; hg19: chr4-71339723; COSMIC: COSV59218861;