chr8-144098948-C-T

Position:

• chr8-144098948-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_030974.4(SHARPIN):​c.1094G>A​(p.Arg365His) variant causes a missense change. The variant allele was found at a frequency of 0.00565 in 1,592,062 control chromosomes in the GnomAD database, including 76 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0049 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0057 (70 hom.)
• Consequence: SHARPIN NM_030974.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.47

Genes affected

SHARPIN (HGNC:25321): (SHANK associated RH domain interactor) Enables polyubiquitin modification-dependent protein binding activity. Involved in protein linear polyubiquitination and regulation of signal transduction. Located in cytosol. Part of LUBAC complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00789538).
• BP6: Variant 8-144098948-C-T is Benign according to our data. Variant chr8-144098948-C-T is described in ClinVar as [Benign]. Clinvar id is 710592.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00486 (740/152250) while in subpopulation SAS AF= 0.0294 (142/4826). AF 95% confidence interval is 0.0255. There are 6 homozygotes in gnomad4. There are 420 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SHARPIN	NM_030974.4	c.1094G>A	p.Arg365His	missense_variant	8/9	ENST00000398712.7	NP_112236.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SHARPIN	ENST00000398712.7	c.1094G>A	p.Arg365His	missense_variant	8/9	1	NM_030974.4	ENSP00000381698	P1
SHARPIN	ENST00000359551.6	c.969G>A	p.Pro323=	synonymous_variant, NMD_transcript_variant	7/8	1		ENSP00000352551
SHARPIN	ENST00000532536.5	c.218G>A	p.Arg73His	missense_variant	3/3	3		ENSP00000432355

Frequencies

GnomAD3 genomes AF: 0.00486 AC: 739 AN: 152132 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.00406

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0290

Gnomad FIN AF: 0.00687

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00494

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.00804 AC: 1816 AN: 225812 Hom.: 12 AF XY: 0.00900 AC XY: 1110 AN XY: 123378

Gnomad AFR exome AF: 0.000670

Gnomad AMR exome AF: 0.00255

Gnomad ASJ exome AF: 0.0162

Gnomad EAS exome AF: 0.000308

Gnomad SAS exome AF: 0.0288

Gnomad FIN exome AF: 0.00802

Gnomad NFE exome AF: 0.00575

Gnomad OTH exome AF: 0.00884

GnomAD4 exome AF: 0.00573 AC: 8254 AN: 1439812 Hom.: 70 Cov.: 31 AF XY: 0.00643 AC XY: 4606 AN XY: 716506

Gnomad4 AFR exome AF: 0.000723

Gnomad4 AMR exome AF: 0.00258

Gnomad4 ASJ exome AF: 0.0170

Gnomad4 EAS exome AF: 0.000152

Gnomad4 SAS exome AF: 0.0279

Gnomad4 FIN exome AF: 0.00687

Gnomad4 NFE exome AF: 0.00412

Gnomad4 OTH exome AF: 0.00700

GnomAD4 genome AF: 0.00486 AC: 740 AN: 152250 Hom.: 6 Cov.: 33 AF XY: 0.00564 AC XY: 420 AN XY: 74442

Gnomad4 AFR AF: 0.000698

Gnomad4 AMR AF: 0.00405

Gnomad4 ASJ AF: 0.0161

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0294

Gnomad4 FIN AF: 0.00687

Gnomad4 NFE AF: 0.00494

Gnomad4 OTH AF: 0.00805

Alfa AF: 0.00529 Hom.: 2

Bravo AF: 0.00352

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000981 AC: 4

ESP6500EA AF: 0.00522 AC: 44

ExAC AF: 0.00805 AC: 974

Asia WGS AF: 0.0110 AC: 38 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 02, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.36	T;D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;D
MetaRNN	Benign	0.0079	T;T
MetaSVM	Benign	-0.39	T
MutationAssessor	Pathogenic	3.1	.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-5.0	D;D
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0080	D;D
Polyphen		1.0	.;D
Vest4		0.49
MVP		0.73
MPC		0.75
ClinPred		0.048	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.45
gMVP		0.72

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: rs112552278; hg19: chr8-145153851; COSMIC: COSV59643901; COSMIC: COSV59643901;