NM_004262.3:c.547T>C

Variant names:

• chr4-67833349-A-G
• rs201995425
• NM_004262.3:c.547T>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004262.3(TMPRSS11D):​c.547T>C​(p.Ser183Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000698 in 1,432,230 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. S183T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: TMPRSS11D NM_004262.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.48
• Publications: 2 publications found

Genes affected

TMPRSS11D (HGNC:24059): (transmembrane serine protease 11D) This gene encodes a trypsin-like serine protease released from the submucosal serous glands onto mucous membrane. It is a type II integral membrane protein and has 29-38% identity in the sequence of the catalytic region with human hepsin, enteropeptidase, acrosin, and mast cell tryptase. The noncatalytic region has little similarity to other known proteins. This protein may play some biological role in the host defense system on the mucous membrane independently of or in cooperation with other substances in airway mucous or bronchial secretions. This protein facilitates entry of viruses into host cells by proteolytically cleaving and activating viral envelope glycoproteins. [provided by RefSeq, Aug 2021]

UBA6-DT (HGNC:49083): (UBA6 divergent transcript)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004262.3. 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
	TMPRSS11D	NM_004262.3	MANE Select	c.547T>C	p.Ser183Pro	missense	Exon 7 of 10	NP_004253.1	O60235

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMPRSS11D	ENST00000283916.11	TSL:1 MANE Select	c.547T>C	p.Ser183Pro	missense	Exon 7 of 10	ENSP00000283916.6	O60235
	TMPRSS11D	ENST00000505533.1	TSL:1	n.279T>C		non_coding_transcript_exon	Exon 1 of 4
	UBA6-DT	ENST00000500538.7	TSL:1	n.1987+78094A>G		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.98e-7 AC: 1 AN: 1432230 Hom.: 0 Cov.: 30 AF XY: 0.00000140 AC XY: 1 AN XY: 712110

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

African (AFR) AF: 0.00 AC: 0 AN: 31716

American (AMR) AF: 0.00 AC: 0 AN: 40286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25194

East Asian (EAS) AF: 0.00 AC: 0 AN: 37354

South Asian (SAS) AF: 0.00 AC: 0 AN: 81642

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52978

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5660

European-Non Finnish (NFE) AF: 9.11e-7 AC: 1 AN: 1098276

Other (OTH) AF: 0.00 AC: 0 AN: 59124

⚠️ 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 Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.032	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.5
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.22
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.016	D
Polyphen		1.0	D
Vest4		0.58
MutPred		0.38		Gain of catalytic residue at L182 (P = 0.1769)
MVP		0.80
MPC		0.53
ClinPred		0.97	D
GERP RS		5.6
Varity_R		0.62
gMVP		0.84
Mutation Taster		=57/43	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: rs201995425; hg19: chr4-68699067;