2-38806693-C-T

Variant names:

• chr2-38806693-C-T
• rs1669955976
• NM_198963.3:c.3682G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_198963.3(DHX57):​c.3682G>A​(p.Val1228Met) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1228L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DHX57 NM_198963.3 missense, splice_region
• Scores: Splicing: ADA: 0.9994
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.83
• Publications: 0 publications found

Genes affected

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198963.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHX57	NM_198963.3	MANE Select	c.3682G>A	p.Val1228Met	missense splice_region	Exon 22 of 24	NP_945314.1	Q6P158-1
	DHX57	NM_001329963.1		c.3376G>A	p.Val1126Met	missense splice_region	Exon 22 of 24	NP_001316892.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHX57	ENST00000457308.6	TSL:1 MANE Select	c.3682G>A	p.Val1228Met	missense splice_region	Exon 22 of 24	ENSP00000405111.2	Q6P158-1
	DHX57	ENST00000620517.4	TSL:1	n.*1980G>A		splice_region non_coding_transcript_exon	Exon 21 of 23	ENSP00000482275.1	A0A087WZ11
	DHX57	ENST00000622155.4	TSL:1	n.4709G>A		splice_region non_coding_transcript_exon	Exon 21 of 23

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.047	T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.0076	T
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		6.8
PrimateAI	Uncertain	0.66	T
Sift4G	Uncertain	0.0060	D
Polyphen		0.99	D
Vest4		0.85
MutPred		0.58		Loss of methylation at K1229 (P = 0.0332)
MVP		0.77
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.28
gMVP		0.69
Mutation Taster		=49/51	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.91
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1669955976; hg19: chr2-39033835;