4-168512175-T-C

Variant names:

• chr4-168512175-T-C
• rs7655494
• NM_001166108.2:c.671T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001166108.2(PALLD):​c.671T>C​(p.Met224Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.309 in 1,613,214 control chromosomes in the GnomAD database, including 78,968 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M224I) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.29 (6562 hom., cov: 32)
  • Exomes 𝑓: 0.31 (72406 hom.)
• Consequence: PALLD NM_001166108.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.328
• Publications: 12 publications found

Genes affected

PALLD (HGNC:17068): (palladin, cytoskeletal associated protein) This gene encodes a cytoskeletal protein that is required for organizing the actin cytoskeleton. The protein is a component of actin-containing microfilaments, and it is involved in the control of cell shape, adhesion, and contraction. Polymorphisms in this gene are associated with a susceptibility to pancreatic cancer type 1, and also with a risk for myocardial infarction. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

DDX60L (HGNC:26429): (DExD/H-box 60 like) This gene encodes a member of the DExD/H-box helicase family of proteins, a subset of the super family 2 helicases. Members of the DExD/H-box helicase family share a conserved functional core comprised of two RecA-like globular domains. These domains contain conserved motifs that mediate ATP binding, ATP hydrolysis, nucleic acid binding, and RNA unwinding. In addition to functions in RNA metabolism, members of this family are involved in anti-viral immunity and act as cytosolic sensors of viral nucleic acids. The protein encoded by this gene has been shown to inhibit hepatitis C virus replication in response to interferon stimulation in cell culture. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2016]

LOC107986198 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001919508).
• BP6: Variant 4-168512175-T-C is Benign according to our data. Variant chr4-168512175-T-C is described in ClinVar as Benign. ClinVar VariationId is 403284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.327 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001166108.2. 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
	PALLD	NM_001166108.2	MANE Select	c.671T>C	p.Met224Thr	missense	Exon 2 of 22	NP_001159580.1
	PALLD	NM_016081.4		c.671T>C	p.Met224Thr	missense	Exon 2 of 21	NP_057165.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PALLD	ENST00000505667.6	TSL:1 MANE Select	c.671T>C	p.Met224Thr	missense	Exon 2 of 22	ENSP00000425556.1
	PALLD	ENST00000261509.10	TSL:1	c.671T>C	p.Met224Thr	missense	Exon 2 of 21	ENSP00000261509.6
	PALLD	ENST00000968439.1		c.671T>C	p.Met224Thr	missense	Exon 2 of 22	ENSP00000638498.1

Frequencies

GnomAD3 genomes AF: 0.293 AC: 44451 AN: 151672 Hom.: 6557 Cov.: 32

Gnomad AFR AF: 0.246

Gnomad AMI AF: 0.388

Gnomad AMR AF: 0.242

Gnomad ASJ AF: 0.281

Gnomad EAS AF: 0.191

Gnomad SAS AF: 0.219

Gnomad FIN AF: 0.394

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.330

Gnomad OTH AF: 0.279

GnomAD2 exomes AF: 0.281 AC: 70338 AN: 250488 AF XY: 0.282

Gnomad AFR exome AF: 0.246

Gnomad AMR exome AF: 0.180

Gnomad ASJ exome AF: 0.297

Gnomad EAS exome AF: 0.176

Gnomad FIN exome AF: 0.399

Gnomad NFE exome AF: 0.325

Gnomad OTH exome AF: 0.295

GnomAD4 exome AF: 0.311 AC: 454118 AN: 1461422 Hom.: 72406 Cov.: 37 AF XY: 0.309 AC XY: 224394 AN XY: 727020

African (AFR) AF: 0.244 AC: 8157 AN: 33454

American (AMR) AF: 0.188 AC: 8419 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.298 AC: 7780 AN: 26130

East Asian (EAS) AF: 0.194 AC: 7705 AN: 39694

South Asian (SAS) AF: 0.225 AC: 19408 AN: 86254

European-Finnish (FIN) AF: 0.393 AC: 20996 AN: 53402

Middle Eastern (MID) AF: 0.239 AC: 1378 AN: 5768

European-Non Finnish (NFE) AF: 0.326 AC: 362339 AN: 1111640

Other (OTH) AF: 0.297 AC: 17936 AN: 60374

GnomAD4 genome AF: 0.293 AC: 44470 AN: 151792 Hom.: 6562 Cov.: 32 AF XY: 0.292 AC XY: 21620 AN XY: 74138

African (AFR) AF: 0.246 AC: 10218 AN: 41454

American (AMR) AF: 0.241 AC: 3686 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.281 AC: 972 AN: 3462

East Asian (EAS) AF: 0.192 AC: 987 AN: 5152

South Asian (SAS) AF: 0.219 AC: 1053 AN: 4818

European-Finnish (FIN) AF: 0.394 AC: 4150 AN: 10538

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.330 AC: 22390 AN: 67796

Other (OTH) AF: 0.276 AC: 582 AN: 2112

Alfa AF: 0.309 Hom.: 15274

Bravo AF: 0.280

TwinsUK AF: 0.308 AC: 1143

ALSPAC AF: 0.333 AC: 1283

ESP6500AA AF: 0.242 AC: 1068

ESP6500EA AF: 0.305 AC: 2621

ExAC AF: 0.285 AC: 34609

Asia WGS AF: 0.196 AC: 683 AN: 3478

EpiCase AF: 0.320

EpiControl AF: 0.315

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Pancreatic cancer, susceptibility to, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.15
DANN	Benign	0.61
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.11	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.6	N
PhyloP100		0.33
PrimateAI	Benign	0.30	T
PROVEAN	Benign	1.0	N
REVEL	Benign	0.052
Sift	Benign	1.0	T
Sift4G	Benign	0.75	T
Vest4		0.010
MPC		0.23
ClinPred		0.0038	T
GERP RS		3.7
gMVP		0.16
Mutation Taster		=99/1	polymorphism (auto)

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: rs7655494; hg19: chr4-169433326; COSMIC: COSV54981247; COSMIC: COSV54981247;