2-38813863-T-C

Position:

• chr2-38813863-T-C

Variant summary

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

The NM_198963.3(DHX57):​c.3639A>G​(p.Ile1213Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,322 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/18 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)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DHX57 NM_198963.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.41

Genes affected

DHX57 (HGNC:20086): (DExH-box helicase 57) Enables RNA binding activity. [provided by Alliance of Genome Resources, Apr 2022]

DHX57 (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=0.22815022).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DHX57	NM_198963.3	c.3639A>G	p.Ile1213Met	missense_variant	21/24	ENST00000457308.6	NP_945314.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DHX57	ENST00000457308.6	c.3639A>G	p.Ile1213Met	missense_variant	21/24	1	NM_198963.3	ENSP00000405111.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461322 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726978

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

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

May 24, 2024

The c.3639A>G (p.I1213M) alteration is located in exon 21 (coding exon 20) of the DHX57 gene. This alteration results from a A to G substitution at nucleotide position 3639, causing the isoleucine (I) at amino acid position 1213 to be replaced by a methionine (M). 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	0.12
BayesDel_addAF	Uncertain	0.055	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.044	T
Eigen	Benign	-0.030
Eigen_PC	Benign	0.081
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.0073	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.74	N
PrimateAI	Uncertain	0.52	T
Sift4G	Benign	0.23	T
Polyphen		0.28	B
Vest4		0.53
MutPred		0.54		Gain of helix (P = 0.0082);
MVP		0.56
ClinPred		0.46	T
GERP RS		4.5
Varity_R		0.087
gMVP		0.61

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: rs1670395163; hg19: chr2-39041005; COSMIC: COSV54889351; COSMIC: COSV54889351;