7-44571636-T-C

Position:

• chr7-44571636-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_019082.4(DDX56):​c.746A>G​(p.Tyr249Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00872 in 1,614,180 control chromosomes in the GnomAD database, including 145 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0062 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0090 (137 hom.)
• Consequence: DDX56 NM_019082.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.66

Genes affected

DDX56 (HGNC:18193): (DEAD-box helicase 56) This gene encodes a member of the DEAD box protein family. DEAD box proteins, characterized by the conserved motif Asp-Glu-Ala-Asp (DEAD), are putative RNA helicases. They are implicated in a number of cellular processes involving alteration of RNA secondary structure such as translation initiation, nuclear and mitochondrial splicing, and ribosome and spliceosome assembly. Based on their distribution patterns, some members of this family are believed to be involved in embryogenesis, spermatogenesis, and cellular growth and division. The protein encoded by this gene shows ATPase activity in the presence of polynucleotides and associates with nucleoplasmic 65S preribosomal particles. This gene may be involved in ribosome synthesis, most likely during assembly of the large 60S ribosomal subunit. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2012]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008875042).
• BP6: Variant 7-44571636-T-C is Benign according to our data. Variant chr7-44571636-T-C is described in ClinVar as [Benign]. Clinvar id is 774874.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00616 (939/152330) while in subpopulation SAS AF= 0.0286 (138/4830). AF 95% confidence interval is 0.0247. There are 8 homozygotes in gnomad4. There are 471 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DDX56	NM_019082.4	c.746A>G	p.Tyr249Cys	missense_variant	6/14	ENST00000258772.10	NP_061955.1
DDX56	NM_001257189.2	c.746A>G	p.Tyr249Cys	missense_variant	6/13		NP_001244118.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DDX56	ENST00000258772.10	c.746A>G	p.Tyr249Cys	missense_variant	6/14	1	NM_019082.4	ENSP00000258772	P1

Frequencies

GnomAD3 genomes AF: 0.00618 AC: 940 AN: 152212 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00142

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0189

Gnomad SAS AF: 0.0285

Gnomad FIN AF: 0.00386

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00804

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00907 AC: 2280 AN: 251444 Hom.: 26 AF XY: 0.0101 AC XY: 1379 AN XY: 135920

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00171

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.0170

Gnomad SAS exome AF: 0.0297

Gnomad FIN exome AF: 0.00393

Gnomad NFE exome AF: 0.00739

Gnomad OTH exome AF: 0.00847

GnomAD4 exome AF: 0.00898 AC: 13129 AN: 1461850 Hom.: 137 Cov.: 34 AF XY: 0.00968 AC XY: 7039 AN XY: 727224

Gnomad4 AFR exome AF: 0.00137

Gnomad4 AMR exome AF: 0.00174

Gnomad4 ASJ exome AF: 0.000612

Gnomad4 EAS exome AF: 0.0303

Gnomad4 SAS exome AF: 0.0287

Gnomad4 FIN exome AF: 0.00437

Gnomad4 NFE exome AF: 0.00758

Gnomad4 OTH exome AF: 0.00851

GnomAD4 genome AF: 0.00616 AC: 939 AN: 152330 Hom.: 8 Cov.: 32 AF XY: 0.00632 AC XY: 471 AN XY: 74490

Gnomad4 AFR AF: 0.00142

Gnomad4 AMR AF: 0.00268

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.0189

Gnomad4 SAS AF: 0.0286

Gnomad4 FIN AF: 0.00386

Gnomad4 NFE AF: 0.00804

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00776 Hom.: 8

Bravo AF: 0.00519

TwinsUK AF: 0.00620 AC: 23

ALSPAC AF: 0.00727 AC: 28

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00826 AC: 71

ExAC AF: 0.00953 AC: 1157

Asia WGS AF: 0.0180 AC: 63 AN: 3478

EpiCase AF: 0.00812

EpiControl AF: 0.00563

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 11, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T;.
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.93	D;D
MetaRNN	Benign	0.0089	T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.92	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-7.8	D;D
REVEL	Benign	0.25
Sift	Benign	0.039	D;D
Sift4G	Uncertain	0.048	D;T
Polyphen		0.75	P;.
Vest4		0.61
MVP		0.32
MPC		0.20
ClinPred		0.042	T
GERP RS		5.8
Varity_R		0.58
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs41279639; hg19: chr7-44611235; COSMIC: COSV99346327; COSMIC: COSV99346327;