4-67822378-T-C

Variant names:

• chr4-67822378-T-C
• rs112453913
• NM_004262.3:c.1216A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004262.3(TMPRSS11D):​c.1216A>G​(p.Thr406Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,638 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TMPRSS11D NM_004262.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.79
• Publications: 0 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3813079).

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.1216A>G	p.Thr406Ala	missense	Exon 10 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.1216A>G	p.Thr406Ala	missense	Exon 10 of 10	ENSP00000283916.6	O60235
	TMPRSS11D	ENST00000505533.1	TSL:1	n.948A>G		non_coding_transcript_exon	Exon 4 of 4
	UBA6-DT	ENST00000500538.7	TSL:1	n.1987+67123T>C		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461638 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727108

⚠️ 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: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111840

Other (OTH) AF: 0.00 AC: 0 AN: 60380

⚠️ 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

ClinVar submissions

Significance: Uncertain significance

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	0.13
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Uncertain	0.79	D
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	-0.92	N
PhyloP100		1.8
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Benign	0.24
Sift	Benign	0.031	D
Sift4G	Uncertain	0.060	T
Polyphen		0.41	B
Vest4		0.20
MutPred		0.62		Gain of glycosylation at Y402 (P = 0.0823)
MVP		0.81
MPC		0.41
ClinPred		0.72	D
GERP RS		1.7
Varity_R		0.20
gMVP		0.79
Mutation Taster		=64/36	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: rs112453913; hg19: chr4-68688096;