3-111884483-A-G

Variant names:

• chr3-111884483-A-G
• rs757190870
• NM_001134438.2:c.406A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001134438.2(PHLDB2):​c.406A>G​(p.Ser136Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,614,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: PHLDB2 NM_001134438.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.607
• Publications: 0 publications found

Genes affected

PHLDB2 (HGNC:29573): (pleckstrin homology like domain family B member 2) Enables cadherin binding activity. Involved in several processes, including negative regulation of focal adhesion assembly; regulation of cytoskeleton organization; and regulation of embryonic development. Located in several cellular components, including basal cortex; cell leading edge; and intermediate filament cytoskeleton. Colocalizes with focal adhesion. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03608486).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001134438.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHLDB2	NM_001134438.2	MANE Select	c.406A>G	p.Ser136Gly	missense	Exon 2 of 18	NP_001127910.1	Q86SQ0-1
	PHLDB2	NM_001134439.2		c.406A>G	p.Ser136Gly	missense	Exon 2 of 18	NP_001127911.1	Q86SQ0-1
	PHLDB2	NM_001134437.2		c.487A>G	p.Ser163Gly	missense	Exon 3 of 18	NP_001127909.1	Q86SQ0-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHLDB2	ENST00000431670.7	TSL:1 MANE Select	c.406A>G	p.Ser136Gly	missense	Exon 2 of 18	ENSP00000405405.2	Q86SQ0-1
	PHLDB2	ENST00000393925.7	TSL:1	c.406A>G	p.Ser136Gly	missense	Exon 2 of 18	ENSP00000377502.3	Q86SQ0-1
	PHLDB2	ENST00000481953.5	TSL:1	c.406A>G	p.Ser136Gly	missense	Exon 1 of 16	ENSP00000418319.1	Q86SQ0-2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152216 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461856 Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4 AN XY: 727240

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111984

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152216 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74360

African (AFR) AF: 0.0000482 AC: 2 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	8.8
DANN	Benign	0.93
DEOGEN2	Benign	0.0068	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.036	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.61
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.92	N
REVEL	Benign	0.046
Sift	Benign	0.15	T
Sift4G	Benign	0.38	T
Polyphen		0.015	B
Vest4		0.21
MutPred		0.24		Gain of glycosylation at Y131 (P = 0.0019)
MVP		0.27
MPC		0.084
ClinPred		0.050	T
GERP RS		-1.5
PromoterAI		0.023	Neutral
Varity_R		0.024
gMVP		0.15
Mutation Taster		=94/6	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: rs757190870; hg19: chr3-111603330;