4-100189947-C-T

Position:

• chr4-100189947-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_145244.4(DDIT4L):​c.37G>A​(p.Ala13Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 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)
• Consequence: DDIT4L NM_145244.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.15

Genes affected

DDIT4L (HGNC:30555): (DNA damage inducible transcript 4 like) Predicted to be involved in negative regulation of signal transduction. Predicted to be located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

H2AZ1-DT (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12557358).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DDIT4L	NM_145244.4	c.37G>A	p.Ala13Thr	missense_variant	2/3	ENST00000273990.6	NP_660287.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DDIT4L	ENST00000273990.6	c.37G>A	p.Ala13Thr	missense_variant	2/3	1	NM_145244.4	ENSP00000354830.2
DDIT4L	ENST00000502763.1	c.37G>A	p.Ala13Thr	missense_variant	1/2	2		ENSP00000427301.1
DDIT4L	ENST00000513992.1	c.37G>A	p.Ala13Thr	missense_variant	2/3	4		ENSP00000427040.1
H2AZ1-DT	ENST00000515026.1	n.730-5118C>T		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Dec 13, 2023

The c.37G>A (p.A13T) alteration is located in exon 2 (coding exon 1) of the DDIT4L gene. This alteration results from a G to A substitution at nucleotide position 37, causing the alanine (A) at amino acid position 13 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	0.079
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0058	T;.;.
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.69	T;T;T
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.41	N;.;.
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.060	N;N;N
REVEL	Benign	0.053
Sift	Benign	0.18	T;T;T
Sift4G	Benign	0.61	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.093
MutPred		0.096		Gain of glycosylation at A13 (P = 0.0238);Gain of glycosylation at A13 (P = 0.0238);Gain of glycosylation at A13 (P = 0.0238);
MVP		0.44
MPC		0.028
ClinPred		0.28	T
GERP RS		3.4
Varity_R		0.058
gMVP		0.27

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: rs1336140622; hg19: chr4-101111104;