chr7-99386686-G-T

Position:

• chr7-99386686-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005720.4(ARPC1B):​c.66G>T​(p.Gln22His) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000246 in 1,461,068 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: ARPC1B NM_005720.4 missense, splice_region
• Scores: Splicing: ADA: 0.00002458
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.39

Genes affected

ARPC1B (HGNC:704): (actin related protein 2/3 complex subunit 1B) This gene encodes one of seven subunits of the human Arp2/3 protein complex. This subunit is a member of the SOP2 family of proteins and is most similar to the protein encoded by gene ARPC1A. The similarity between these two proteins suggests that they both may function as p41 subunit of the human Arp2/3 complex that has been implicated in the control of actin polymerization in cells. It is possible that the p41 subunit is involved in assembling and maintaining the structure of the Arp2/3 complex. Multiple versions of the p41 subunit may adapt the functions of the complex to different cell types or developmental stages. This protein also has a role in centrosomal homeostasis by being an activator and substrate of the Aurora A kinase. [provided by RefSeq, Mar 2011]

ENSG00000284292 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.785

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARPC1B	NM_005720.4	c.66G>T	p.Gln22His	missense_variant, splice_region_variant	3/10	ENST00000646101.2	NP_005711.1
ARPC1B	XM_024446628.2	c.66G>T	p.Gln22His	missense_variant, splice_region_variant	3/10		XP_024302396.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARPC1B	ENST00000646101.2	c.66G>T	p.Gln22His	missense_variant, splice_region_variant	3/10		NM_005720.4	ENSP00000496599.1
ENSG00000284292	ENST00000638617.1	c.1062G>T	p.Gln354His	missense_variant, splice_region_variant	10/17	5		ENSP00000491073.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000246 AC: 36 AN: 1461068 Hom.: 0 Cov.: 30 AF XY: 0.0000234 AC XY: 17 AN XY: 726914

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000288

Gnomad4 OTH exome AF: 0.0000663

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 08, 2022

This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 22 of the ARPC1B protein (p.Gln22His). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ARPC1B-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.086	.;T;.;T;T;T;.;.;.;T;T;T;T;T
Eigen	Benign	0.053
Eigen_PC	Benign	-0.056
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.83	T;T;T;.;.;.;D;D;T;.;.;.;.;T
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.78	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.46	T
MutationAssessor	Pathogenic	3.0	.;.;.;M;M;M;.;.;.;M;M;M;M;M
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.7	.;D;D;.;D;D;D;.;D;D;D;D;D;.
REVEL	Uncertain	0.39
Sift	Benign	0.097	.;T;T;.;D;T;D;.;T;T;T;D;T;.
Sift4G	Benign	0.16	.;T;T;.;T;T;D;.;T;T;T;T;T;.
Polyphen		1.0	.;.;.;D;D;D;.;.;.;D;D;D;D;D
Vest4		0.73
MutPred		0.41		.;Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);
MVP		0.74
MPC		0.97
ClinPred		0.94	D
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.43
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000025
dbscSNV1_RF	Benign	0.0
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: rs1250940667; hg19: chr7-98984309;