4-100187994-C-T

Variant names:

• chr4-100187994-C-T
• NM_145244.4:c.265G>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_145244.4(DDIT4L):​c.265G>A​(p.Ala89Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DDIT4L NM_145244.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.36

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:40271): (H2AZ1 divergent transcript)

ACMG classification

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, 0.858

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DDIT4L	NM_145244.4	c.265G>A	p.Ala89Thr	missense_variant	Exon 3 of 3	ENST00000273990.6	NP_660287.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DDIT4L	ENST00000273990.6	c.265G>A	p.Ala89Thr	missense_variant	Exon 3 of 3	1	NM_145244.4	ENSP00000354830.2
DDIT4L	ENST00000502763.1	c.265G>A	p.Ala89Thr	missense_variant	Exon 2 of 2	2		ENSP00000427301.1
DDIT4L	ENST00000513992.1	c.265G>A	p.Ala89Thr	missense_variant	Exon 3 of 3	4		ENSP00000427040.1
H2AZ1-DT	ENST00000515026.1	n.730-7071C>T		intron_variant	Intron 5 of 5	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.265G>A (p.A89T) alteration is located in exon 3 (coding exon 2) of the DDIT4L gene. This alteration results from a G to A substitution at nucleotide position 265, causing the alanine (A) at amino acid position 89 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	Pathogenic	0.67
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.23	T;.;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Benign	-0.29	T
MutationAssessor	Uncertain	2.5	M;.;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.8	D;D;D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0080	D;D;D
Sift4G	Uncertain	0.013	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.71
MutPred		0.75		Gain of disorder (P = 0.0486);Gain of disorder (P = 0.0486);Gain of disorder (P = 0.0486);
MVP		0.83
MPC		0.20
ClinPred		0.98	D
GERP RS		5.6
Varity_R		0.43
gMVP		0.62

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: chr4-101109151;