chr22-19724242-C-T

Variant names:

• chr22-19724242-C-T
• rs142352780
• NM_000407.5:c.399C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_000407.5(GP1BB):​c.399C>T​(p.Ala133Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00577 in 1,240,568 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A133A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0046 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0059 (21 hom.)
• Consequence: GP1BB NM_000407.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -5.28
• Publications: 1 publications found

Genes affected

GP1BB (HGNC:4440): (glycoprotein Ib platelet subunit beta) Platelet glycoprotein Ib (GPIb) is a heterodimeric transmembrane protein consisting of a disulfide-linked 140 kD alpha chain and 22 kD beta chain. It is part of the GPIb-V-IX system that constitutes the receptor for von Willebrand factor (VWF), and mediates platelet adhesion in the arterial circulation. GPIb alpha chain provides the VWF binding site, and GPIb beta contributes to surface expression of the receptor and participates in transmembrane signaling through phosphorylation of its intracellular domain. Mutations in the GPIb beta subunit have been associated with Bernard-Soulier syndrome, velocardiofacial syndrome and giant platelet disorder. The 206 amino acid precursor of GPIb beta is synthesized from a 1.0 kb mRNA expressed in plateletes and megakaryocytes. A 411 amino acid protein arising from a longer, unspliced transcript in endothelial cells has been described; however, the authenticity of this product has been questioned. Yet another less abundant GPIb beta mRNA species of 3.5 kb, expressed in nonhematopoietic tissues such as endothelium, brain and heart, was shown to result from inefficient usage of a non-consensus polyA signal in the neighboring upstream gene (SEPT5, septin 5). In the absence of polyadenylation from its own imperfect site, the SEPT5 gene produces read-through transcripts that use the consensus polyA signal of this gene. [provided by RefSeq, Dec 2010]

ENSG00000284874 (HGNC:):

SEPTIN5 (HGNC:9164): (septin 5) This gene is a member of the septin gene family of nucleotide binding proteins, originally described in yeast as cell division cycle regulatory proteins. Septins are highly conserved in yeast, Drosophila, and mouse and appear to regulate cytoskeletal organization. Disruption of septin function disturbs cytokinesis and results in large multinucleate or polyploid cells. This gene is mapped to 22q11, the region frequently deleted in DiGeorge and velocardiofacial syndromes. A translocation involving the MLL gene and this gene has also been reported in patients with acute myeloid leukemia. Alternative splicing results in multiple transcript variants. The presence of a non-consensus polyA signal (AACAAT) in this gene also results in read-through transcription into the downstream neighboring gene (GP1BB; platelet glycoprotein Ib), whereby larger, non-coding transcripts are produced. [provided by RefSeq, Dec 2010]

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 22-19724242-C-T is Benign according to our data. Variant chr22-19724242-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 256031.
• BP7: Synonymous conserved (PhyloP=-5.28 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00463 (700/151136) while in subpopulation NFE AF = 0.00658 (445/67598). AF 95% confidence interval is 0.00608. There are 1 homozygotes in GnomAd4. There are 346 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 21 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000407.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GP1BB	NM_000407.5	MANE Select	c.399C>T	p.Ala133Ala	synonymous	Exon 2 of 2	NP_000398.1
	SEPT5-GP1BB	NR_037611.1		n.4139C>T		non_coding_transcript_exon	Exon 12 of 12
	SEPT5-GP1BB	NR_037612.1		n.2643C>T		non_coding_transcript_exon	Exon 12 of 12

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GP1BB	ENST00000366425.4	TSL:1 MANE Select	c.399C>T	p.Ala133Ala	synonymous	Exon 2 of 2	ENSP00000383382.2
	ENSG00000284874	ENST00000431044.5	TSL:1	n.*1484C>T		non_coding_transcript_exon	Exon 12 of 12	ENSP00000399685.1
	ENSG00000284874	ENST00000431044.5	TSL:1	n.*1484C>T		3_prime_UTR	Exon 12 of 12	ENSP00000399685.1

Frequencies

GnomAD3 genomes AF: 0.00464 AC: 701 AN: 151028 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00114

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00435

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00289

Gnomad FIN AF: 0.0114

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.00660

Gnomad OTH AF: 0.00530

GnomAD2 exomes AF: 0.00716 AC: 11 AN: 1536 AF XY: 0.00549

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad FIN exome AF: 0.00932

Gnomad NFE exome AF: 0.00701

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00593 AC: 6457 AN: 1089432 Hom.: 21 Cov.: 31 AF XY: 0.00592 AC XY: 3075 AN XY: 519468

African (AFR) AF: 0.000955 AC: 21 AN: 21980

American (AMR) AF: 0.00530 AC: 40 AN: 7554

Ashkenazi Jewish (ASJ) AF: 0.000150 AC: 2 AN: 13366

East Asian (EAS) AF: 0.00 AC: 0 AN: 24058

South Asian (SAS) AF: 0.00267 AC: 67 AN: 25100

European-Finnish (FIN) AF: 0.0105 AC: 238 AN: 22642

Middle Eastern (MID) AF: 0.00243 AC: 7 AN: 2882

European-Non Finnish (NFE) AF: 0.00633 AC: 5880 AN: 928614

Other (OTH) AF: 0.00467 AC: 202 AN: 43236

GnomAD4 genome AF: 0.00463 AC: 700 AN: 151136 Hom.: 1 Cov.: 33 AF XY: 0.00468 AC XY: 346 AN XY: 73854

African (AFR) AF: 0.00113 AC: 47 AN: 41452

American (AMR) AF: 0.00435 AC: 66 AN: 15188

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4834

European-Finnish (FIN) AF: 0.0114 AC: 115 AN: 10128

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.00658 AC: 445 AN: 67598

Other (OTH) AF: 0.00525 AC: 11 AN: 2096

Alfa AF: 0.00138 Hom.: 0

Bravo AF: 0.00411

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	1.0
DANN	Benign	0.89
PhyloP100		-5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs142352780; hg19: chr22-19711765;