20-34075911-G-A

Variant summary

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

The NM_016732.3(RALY):c.415G>A(p.Val139Met) variant causes a missense change. The variant allele was found at a frequency of 0.0013 in 1,614,062 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0070 (13 hom., cov: 32)
  • Exomes 𝑓: 0.00071 (13 hom.)
• Consequence: RALY NM_016732.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 6.01

Genes affected

RALY (HGNC:15921): (RALY heterogeneous nuclear ribonucleoprotein) This gene encodes a member of the heterogeneous nuclear ribonucleoprotein (hnRNP) gene family. This protein may play a role in pre-mRNA splicing and in embryonic development. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Sep 2011]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007173568).
• BP6: Variant 20-34075911-G-A is Benign according to our data. Variant chr20-34075911-G-A is described in ClinVar as [Benign]. Clinvar id is 786970.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00697 (1061/152304) while in subpopulation AFR AF= 0.0236 (982/41572). AF 95% confidence interval is 0.0224. There are 13 homozygotes in gnomad4. There are 497 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RALY	NM_016732.3	c.415G>A	p.Val139Met	missense_variant	6/10	ENST00000246194.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RALY	ENST00000246194.8	c.415G>A	p.Val139Met	missense_variant	6/10	1	NM_016732.3	P3

Frequencies

GnomAD3 genomes AF: 0.00697 AC: 1060 AN: 152186 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0237

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00406

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00164 AC: 411 AN: 250868 Hom.: 1 AF XY: 0.00114 AC XY: 154 AN XY: 135670

Gnomad AFR exome AF: 0.0223

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.000980

GnomAD4 exome AF: 0.000705 AC: 1031 AN: 1461758 Hom.: 13 Cov.: 30 AF XY: 0.000606 AC XY: 441 AN XY: 727180

Gnomad4 AFR exome AF: 0.0246

Gnomad4 AMR exome AF: 0.00141

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000252

Gnomad4 OTH exome AF: 0.00177

GnomAD4 genome AF: 0.00697 AC: 1061 AN: 152304 Hom.: 13 Cov.: 32 AF XY: 0.00667 AC XY: 497 AN XY: 74462

Gnomad4 AFR AF: 0.0236

Gnomad4 AMR AF: 0.00405

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00123 Hom.: 1

Bravo AF: 0.00820

ESP6500AA AF: 0.0225 AC: 99

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00205 AC: 249

Asia WGS AF: 0.00173 AC: 7 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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

Invitae

May 16, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
Cadd	Pathogenic	27
Dann	Uncertain	1.0
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.94	D;D;D;D;D
MetaRNN	Benign	0.0072	T;T;T;T;T
MetaSVM	Benign	-1.2	T
MutationTaster	Benign	0.98	D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.51	N;N;N;N;N
REVEL	Benign	0.15
Sift	Uncertain	0.0080	D;D;D;T;T
Sift4G	Benign	0.17	T;T;T;T;T
Polyphen		0.99	D;.;D;.;.
Vest4		0.54
MVP		0.31
MPC		1.4
ClinPred		0.023	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.051
gMVP		0.44

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: rs35191085; hg19: chr20-32663717;