3-195784460-A-T

Variant names:

• chr3-195784460-A-T
• rs56359992
• NM_018406.7:c.7120T>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_018406.7(MUC4):​c.7120T>A​(p.Ser2374Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign 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. S2374P) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.010 (12 hom., cov: 0)
  • Exomes 𝑓: 0.00077 (22 hom.)
  • Failed GnomAD Quality Control
• Consequence: MUC4 NM_018406.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.08
• Publications: 17 publications found

Genes affected

MUC4 (HGNC:7514): (mucin 4, cell surface associated) The major constituents of mucus, the viscous secretion that covers epithelial surfaces such as those in the trachea, colon, and cervix, are highly glycosylated proteins called mucins. These glycoproteins play important roles in the protection of the epithelial cells and have been implicated in epithelial renewal and differentiation. This gene encodes an integral membrane glycoprotein found on the cell surface, although secreted isoforms may exist. At least two dozen transcript variants of this gene have been found, although for many of them the full-length transcript has not been determined or they are found only in tumor tissues. This gene contains a region in the coding sequence which has a variable number (>100) of 48 nt tandem repeats. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0072362423).
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MUC4	NM_018406.7	c.7120T>A	p.Ser2374Thr	missense_variant	Exon 2 of 25	ENST00000463781.8	NP_060876.5
MUC4	NM_004532.6	c.83-6005T>A		intron_variant	Intron 1 of 23		NP_004523.3
MUC4	NM_138297.5	c.83-10155T>A		intron_variant	Intron 1 of 22		NP_612154.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MUC4	ENST00000463781.8	c.7120T>A	p.Ser2374Thr	missense_variant	Exon 2 of 25	5	NM_018406.7	ENSP00000417498.3

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 644 AN: 63698 Hom.: 12 Cov.: 0

Gnomad AFR AF: 0.0286

Gnomad AMI AF: 0.00287

Gnomad AMR AF: 0.00350

Gnomad ASJ AF: 0.00319

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00182

Gnomad FIN AF: 0.000770

Gnomad MID AF: 0.00575

Gnomad NFE AF: 0.00291

Gnomad OTH AF: 0.0103

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000772 AC: 445 AN: 576498 Hom.: 22 Cov.: 295 AF XY: 0.000773 AC XY: 216 AN XY: 279444

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

African (AFR) AF: 0.0160 AC: 152 AN: 9520

American (AMR) AF: 0.000935 AC: 8 AN: 8554

Ashkenazi Jewish (ASJ) AF: 0.000614 AC: 4 AN: 6514

East Asian (EAS) AF: 0.00 AC: 0 AN: 4588

South Asian (SAS) AF: 0.000494 AC: 14 AN: 28352

European-Finnish (FIN) AF: 0.000754 AC: 7 AN: 9284

Middle Eastern (MID) AF: 0.000867 AC: 2 AN: 2306

European-Non Finnish (NFE) AF: 0.000475 AC: 231 AN: 486690

Other (OTH) AF: 0.00130 AC: 27 AN: 20690

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0101 AC: 644 AN: 63752 Hom.: 12 Cov.: 0 AF XY: 0.00986 AC XY: 304 AN XY: 30836

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

African (AFR) AF: 0.0285 AC: 516 AN: 18116

American (AMR) AF: 0.00349 AC: 21 AN: 6010

Ashkenazi Jewish (ASJ) AF: 0.00319 AC: 4 AN: 1254

East Asian (EAS) AF: 0.00 AC: 0 AN: 1712

South Asian (SAS) AF: 0.00183 AC: 4 AN: 2184

European-Finnish (FIN) AF: 0.000770 AC: 3 AN: 3898

Middle Eastern (MID) AF: 0.00617 AC: 1 AN: 162

European-Non Finnish (NFE) AF: 0.00291 AC: 85 AN: 29184

Other (OTH) AF: 0.0102 AC: 9 AN: 884

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 6564

ExAC AF: 0.000243 AC: 15

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.34
DANN	Benign	0.17
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.00058	N
LIST_S2	Benign	0.44	T;T
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.0072	T;T
MetaSVM	Benign	-1.0	T
PhyloP100		-2.1
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.10	N;N
REVEL	Benign	0.0040
Sift	Benign	0.67	T;T
Sift4G	Uncertain	0.021	D;D
Vest4		0.097
MVP		0.014
ClinPred		0.030	T
gMVP		0.00099
Mutation Taster		=100/0	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: rs56359992; hg19: chr3-195511331;