chrX-14020459-C-A

Variant names:

• chrX-14020459-C-A
• rs61740319
• NM_001042479.2:c.91G>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001042479.2(GEMIN8):​c.91G>T​(p.Ala31Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00812 in 1,205,727 control chromosomes in the GnomAD database, including 41 homozygotes. There are 3,075 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0061 (2 hom., 200 hem., cov: 23)
  • Exomes 𝑓: 0.0083 (39 hom. 2875 hem.)
• Consequence: GEMIN8 NM_001042479.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.98

Genes affected

GEMIN8 (HGNC:26044): (gem nuclear organelle associated protein 8) The protein encoded by this gene is part of the SMN complex, which is necessary for spliceosomal snRNP assembly in the cytoplasm and pre-mRNA splicing in the nucleus. The encoded protein binds to both SMN1 and the GEMIN6/GEMIN7 heterodimer, mediating their interaction. This protein is found in nuclear Gemini of Cajal bodies (gems) and in the cytoplasm. Three transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, May 2010]

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008584619).
• BP6: Variant X-14020459-C-A is Benign according to our data. Variant chrX-14020459-C-A is described in ClinVar as [Benign]. Clinvar id is 719272.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-14020459-C-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GEMIN8	NM_001042479.2	c.91G>T	p.Ala31Ser	missense_variant	Exon 4 of 5	ENST00000680255.1	NP_001035944.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GEMIN8	ENST00000680255.1	c.91G>T	p.Ala31Ser	missense_variant	Exon 4 of 5		NM_001042479.2	ENSP00000505429.1

Frequencies

GnomAD3 genomes AF: 0.00609 AC: 682 AN: 112024 Hom.: 2 Cov.: 23

Gnomad AFR AF: 0.00107

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00160

Gnomad ASJ AF: 0.00642

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000747

Gnomad FIN AF: 0.00998

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0103

Gnomad OTH AF: 0.00332

GnomAD2 exomes AF: 0.00597 AC: 1094 AN: 183402 AF XY: 0.00603

Gnomad AFR exome AF: 0.000760

Gnomad AMR exome AF: 0.00106

Gnomad ASJ exome AF: 0.0110

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00743

Gnomad NFE exome AF: 0.0100

Gnomad OTH exome AF: 0.00486

GnomAD4 exome AF: 0.00832 AC: 9104 AN: 1093653 Hom.: 39 Cov.: 28 AF XY: 0.00800 AC XY: 2875 AN XY: 359173

Gnomad4 AFR exome AF: 0.00110 AC: 29 AN: 26315

Gnomad4 AMR exome AF: 0.00134 AC: 47 AN: 35205

Gnomad4 ASJ exome AF: 0.00945 AC: 183 AN: 19355

Gnomad4 EAS exome AF: 0.0000331 AC: 1 AN: 30196

Gnomad4 SAS exome AF: 0.000611 AC: 33 AN: 54039

Gnomad4 FIN exome AF: 0.00738 AC: 299 AN: 40526

Gnomad4 NFE exome AF: 0.00972 AC: 8144 AN: 837968

Gnomad4 Remaining exome AF: 0.00753 AC: 346 AN: 45927

GnomAD4 genome AF: 0.00609 AC: 682 AN: 112074 Hom.: 2 Cov.: 23 AF XY: 0.00584 AC XY: 200 AN XY: 34244

Gnomad4 AFR AF: 0.00107 AC: 0.0010691 AN: 0.0010691

Gnomad4 AMR AF: 0.00160 AC: 0.00160256 AN: 0.00160256

Gnomad4 ASJ AF: 0.00642 AC: 0.00641509 AN: 0.00641509

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000750 AC: 0.000749625 AN: 0.000749625

Gnomad4 FIN AF: 0.00998 AC: 0.00997547 AN: 0.00997547

Gnomad4 NFE AF: 0.0103 AC: 0.0102883 AN: 0.0102883

Gnomad4 OTH AF: 0.00328 AC: 0.00328084 AN: 0.00328084

Alfa AF: 0.00543 Hom.: 39

Bravo AF: 0.00509

TwinsUK AF: 0.00809 AC: 30

ALSPAC AF: 0.0118 AC: 34

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.0109 AC: 73

ExAC AF: 0.00625 AC: 759

EpiCase AF: 0.0104

EpiControl AF: 0.00877

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.025	T;T;T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	.;D;D
MetaRNN	Benign	0.0086	T;T;T
MetaSVM	Benign	-0.48	T
MutationAssessor	Uncertain	2.5	M;M;.
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Benign	0.23
Sift	Uncertain	0.018	D;D;D
Sift4G	Benign	0.081	T;T;T
Polyphen		1.0	D;D;.
Vest4		0.21
MVP		0.38
MPC		0.95
ClinPred		0.016	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.41
gMVP		0.46
Mutation Taster		=96/4	polymorphism (auto)

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: rs61740319; hg19: chrX-14038578; COSMIC: COSV60551575;