NM_001134438.2:c.535A>G

Variant names:

• chr3-111884612-A-G
• rs974459206
• NM_001134438.2:c.535A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001134438.2(PHLDB2):​c.535A>G​(p.Met179Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PHLDB2 NM_001134438.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.63
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23460543).

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.535A>G	p.Met179Val	missense	Exon 2 of 18	NP_001127910.1	Q86SQ0-1
	PHLDB2	NM_001134439.2		c.535A>G	p.Met179Val	missense	Exon 2 of 18	NP_001127911.1	Q86SQ0-1
	PHLDB2	NM_001134437.2		c.616A>G	p.Met206Val	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.535A>G	p.Met179Val	missense	Exon 2 of 18	ENSP00000405405.2	Q86SQ0-1
	PHLDB2	ENST00000393925.7	TSL:1	c.535A>G	p.Met179Val	missense	Exon 2 of 18	ENSP00000377502.3	Q86SQ0-1
	PHLDB2	ENST00000481953.5	TSL:1	c.535A>G	p.Met179Val	missense	Exon 1 of 16	ENSP00000418319.1	Q86SQ0-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461864 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727224

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

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	0.088
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.034	T
Eigen	Benign	0.0092
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		6.6
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.76	N
REVEL	Benign	0.066
Sift	Benign	0.043	D
Sift4G	Benign	0.51	T
Polyphen		0.013	B
Vest4		0.58
MutPred		0.26		Gain of glycosylation at S175 (P = 0.0272)
MVP		0.54
MPC		0.096
ClinPred		0.73	D
GERP RS		4.3
PromoterAI		0.14	Neutral
Varity_R		0.21
gMVP		0.35
Mutation Taster		=88/12	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: rs974459206; hg19: chr3-111603459;