4-68229479-T-C

Position:

• chr4-68229479-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000332644.6(TMPRSS11B):​c.724A>G​(p.Ile242Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.768 in 1,612,296 control chromosomes in the GnomAD database, including 481,149 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.70 (39299 hom., cov: 32)
  • Exomes 𝑓: 0.77 (441850 hom.)
• Consequence: TMPRSS11B ENST00000332644.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.52

Genes affected

TMPRSS11B (HGNC:25398): (transmembrane serine protease 11B) Enables serine-type peptidase activity. Predicted to be involved in proteolysis. Located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.245127E-7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.968 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMPRSS11B	NM_182502.3	c.724A>G	p.Ile242Val	missense_variant	8/10	ENST00000332644.6	NP_872308.2
TMPRSS11B	XM_011531608.3	c.724A>G	p.Ile242Val	missense_variant	8/11		XP_011529910.1
TMPRSS11B	XM_011531609.1	c.687-127A>G		intron_variant			XP_011529911.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMPRSS11B	ENST00000332644.6	c.724A>G	p.Ile242Val	missense_variant	8/10	1	NM_182502.3	ENSP00000330475	P1
TMPRSS11B	ENST00000510856.1	n.200A>G		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes AF: 0.705 AC: 107069 AN: 151940 Hom.: 39286 Cov.: 32

Gnomad AFR AF: 0.518

Gnomad AMI AF: 0.802

Gnomad AMR AF: 0.641

Gnomad ASJ AF: 0.701

Gnomad EAS AF: 0.991

Gnomad SAS AF: 0.874

Gnomad FIN AF: 0.828

Gnomad MID AF: 0.652

Gnomad NFE AF: 0.779

Gnomad OTH AF: 0.696

GnomAD3 exomes AF: 0.752 AC: 188558 AN: 250592 Hom.: 73076 AF XY: 0.766 AC XY: 103779 AN XY: 135474

Gnomad AFR exome AF: 0.508

Gnomad AMR exome AF: 0.551

Gnomad ASJ exome AF: 0.701

Gnomad EAS exome AF: 0.995

Gnomad SAS exome AF: 0.862

Gnomad FIN exome AF: 0.826

Gnomad NFE exome AF: 0.771

Gnomad OTH exome AF: 0.730

GnomAD4 exome AF: 0.774 AC: 1130356 AN: 1460238 Hom.: 441850 Cov.: 37 AF XY: 0.777 AC XY: 564744 AN XY: 726430

Gnomad4 AFR exome AF: 0.515

Gnomad4 AMR exome AF: 0.561

Gnomad4 ASJ exome AF: 0.699

Gnomad4 EAS exome AF: 0.997

Gnomad4 SAS exome AF: 0.863

Gnomad4 FIN exome AF: 0.823

Gnomad4 NFE exome AF: 0.776

Gnomad4 OTH exome AF: 0.759

GnomAD4 genome AF: 0.704 AC: 107114 AN: 152058 Hom.: 39299 Cov.: 32 AF XY: 0.711 AC XY: 52841 AN XY: 74324

Gnomad4 AFR AF: 0.517

Gnomad4 AMR AF: 0.641

Gnomad4 ASJ AF: 0.701

Gnomad4 EAS AF: 0.991

Gnomad4 SAS AF: 0.876

Gnomad4 FIN AF: 0.828

Gnomad4 NFE AF: 0.779

Gnomad4 OTH AF: 0.697

Alfa AF: 0.759 Hom.: 108527

Bravo AF: 0.679

TwinsUK AF: 0.781 AC: 2895

ALSPAC AF: 0.779 AC: 3003

ESP6500AA AF: 0.523 AC: 2303

ESP6500EA AF: 0.779 AC: 6697

ExAC AF: 0.756 AC: 91755

Asia WGS AF: 0.857 AC: 2981 AN: 3476

EpiCase AF: 0.756

EpiControl AF: 0.755

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	17
DANN	Benign	0.67
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.59	T
MetaRNN	Benign	9.2e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.28	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.34	N
REVEL	Benign	0.12
Sift	Benign	0.61	T
Sift4G	Benign	0.57	T
Polyphen		0.0030	B
Vest4		0.047
MPC		0.026
ClinPred		0.0038	T
GERP RS		0.64
Varity_R		0.056
gMVP		0.32

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

Publications

LitVar

Other links and lift over

dbSNP: rs12331141; hg19: chr4-69095197;