11-83198554-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001300975.2(ANKRD42):c.134T>C(p.Ile45Thr) 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 1,461,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I45V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ANKRD42 NM_001300975.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.14

Genes affected

ANKRD42 (HGNC:26752): (ankyrin repeat domain 42) Predicted to enable NF-kappaB binding activity. Predicted to act upstream of or within positive regulation of NF-kappaB transcription factor activity and positive regulation of cytokine production involved in inflammatory response. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41988653).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANKRD42	NM_001300975.2	c.134T>C	p.Ile45Thr	missense_variant	2/11	ENST00000533342.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANKRD42	ENST00000533342.6	c.134T>C	p.Ile45Thr	missense_variant	2/11	1	NM_001300975.2	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461640 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727128

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 11, 2022

The c.134T>C (p.I45T) alteration is located in exon 2 (coding exon 2) of the ANKRD42 gene. This alteration results from a T to C substitution at nucleotide position 134, causing the isoleucine (I) at amino acid position 45 to be replaced by a threonine (T). 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	Benign	0.20
BayesDel_addAF	Benign	-0.00096	T
BayesDel_noAF	Benign	-0.24
Cadd	Benign	22
Dann	Uncertain	0.99
Eigen	Benign	0.11
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.90	D;D;D;D;T;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.42	T;T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.96	L;.;.;.;L;.
MutationTaster	Benign	1.0	D;N;N;N;N;N;N
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.4	N;N;N;N;N;N
REVEL	Benign	0.15
Sift	Uncertain	0.0010	D;D;D;D;T;D
Sift4G	Benign	0.27	T;D;T;D;D;D
Polyphen		0.80	P;.;.;.;P;P
Vest4		0.69
MutPred		0.72		Loss of stability (P = 0.0047);Loss of stability (P = 0.0047);Loss of stability (P = 0.0047);Loss of stability (P = 0.0047);Loss of stability (P = 0.0047);Loss of stability (P = 0.0047);
MVP		0.69
MPC		0.26
ClinPred		0.71	D
GERP RS		3.5
Varity_R		0.085
gMVP		0.37

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-82909596;