5-172203265-T-A

Variant names:

• chr5-172203265-T-A
• rs1191152667
• NM_001171183.2:c.514T>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001171183.2(EFCAB9):​c.514T>A​(p.Leu172Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000506 in 1,384,488 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 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: 0.0000051 (0 hom.)
• Consequence: EFCAB9 NM_001171183.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.573

Genes affected

EFCAB9 (HGNC:34530): (EF-hand calcium binding domain 9) This gene encodes a protein with a C-terminal EF-hand calcium-binding domain similar to that found in penta-EF-hand (PEF) protein family members. The EF-hand is a helix-loop-helix structure with a canonical twelve-residue sequence that coordinates a calcium molecule with pentagonal bipyramidal symmetry. [provided by RefSeq, Jul 2017]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.055332094).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EFCAB9	NM_001171183.2	c.514T>A	p.Leu172Ile	missense_variant	Exon 4 of 4	ENST00000398186.5	NP_001164654.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EFCAB9	ENST00000398186.5	c.514T>A	p.Leu172Ile	missense_variant	Exon 4 of 4	3	NM_001171183.2	ENSP00000381247.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000282 AC: 4 AN: 141798 Hom.: 0 AF XY: 0.0000132 AC XY: 1 AN XY: 75920

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000377

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000506 AC: 7 AN: 1384488 Hom.: 0 Cov.: 32 AF XY: 0.00000146 AC XY: 1 AN XY: 683208

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000196

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 04, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.514T>A (p.L172I) alteration is located in exon 4 (coding exon 4) of the EFCAB9 gene. This alteration results from a T to A substitution at nucleotide position 514, causing the leucine (L) at amino acid position 172 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	12
DANN	Uncertain	0.98
DEOGEN2	Benign	0.016	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.055	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.017
Sift	Benign	0.34	T
Sift4G	Benign	0.39	T
Vest4		0.17
MutPred		0.21		Gain of methylation at K177 (P = 0.0493);
MVP		0.030
ClinPred		0.082	T
GERP RS		2.3
Varity_R		0.046
gMVP		0.082

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

Publications

LitVar

Other links and lift over

dbSNP: rs1191152667; hg19: chr5-171630269;