19-4652203-G-C

Position:

chr19-4652203-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The ENST00000327473.9(TNFAIP8L1):c.334G>C(p.Asp112His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000907 in 1,544,160 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000079 ( 0 hom. )

Consequence

TNFAIP8L1
ENST00000327473.9 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.48

Variant links:

Genes affected

TNFAIP8L1 (HGNC:28279): (TNF alpha induced protein 8 like 1) Enables identical protein binding activity. Predicted to be involved in negative regulation of TOR signaling. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

TNFAIP8L1 links:

MYDGF (HGNC:16948): (myeloid derived growth factor) The protein encoded by this gene was previously thought to support proliferation of lymphoid cells and was considered an interleukin. However, this activity has not been reproducible and the function of this protein is currently unknown. [provided by RefSeq, Jul 2008]

MYDGF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.892

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TNFAIP8L1	NM_152362.3 linkuse as main transcript	c.334G>C	p.Asp112His	missense_variant	2/2	ENST00000327473.9	NP_689575.2
TNFAIP8L1	NM_001167942.1 linkuse as main transcript	c.334G>C	p.Asp112His	missense_variant	2/2		NP_001161414.1
TNFAIP8L1	XM_005259487.4 linkuse as main transcript	c.334G>C	p.Asp112His	missense_variant	2/2		XP_005259544.1
TNFAIP8L1	XM_011527680.3 linkuse as main transcript	c.334G>C	p.Asp112His	missense_variant	2/2		XP_011525982.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
TNFAIP8L1	ENST00000327473.9 linkuse as main transcript	c.334G>C	p.Asp112His	missense_variant	2/2	1	NM_152362.3	ENSP00000331827	P1
TNFAIP8L1	ENST00000536716.1 linkuse as main transcript	c.334G>C	p.Asp112His	missense_variant	2/2	2		ENSP00000444215	P1
MYDGF	ENST00000599761.5 linkuse as main transcript	c.186+7728C>G		intron_variant		3		ENSP00000469136

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000134

AC:

AN:

149060

Hom.:

AF XY:

0.0000124

AC XY:

AN XY:

80590

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000337

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000790

AC:

AN:

1391906

Hom.:

Cov.:

AF XY:

0.00000874

AC XY:

AN XY:

686618

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000834

Gnomad4 OTH exome

AF:

0.0000346

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152254

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000337

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 17, 2021

The c.334G>C (p.D112H) alteration is located in exon 2 (coding exon 1) of the TNFAIP8L1 gene. This alteration results from a G to C substitution at nucleotide position 334, causing the aspartic acid (D) at amino acid position 112 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.38

T;T

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

.;D

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.89

D;D

MetaSVM

Uncertain

-0.23

MutationAssessor

Pathogenic

3.3

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-6.1

D;D

REVEL

Pathogenic

0.70

Sift

Uncertain

0.023

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;D

Vest4

0.89

MutPred

0.72

Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);

MVP

0.092

MPC

2.2

ClinPred

0.97

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.74

gMVP

0.85

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over