14-54760372-C-T

Position:

• chr14-54760372-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015589.6(SAMD4A):​c.1388C>T​(p.Pro463Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 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: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SAMD4A NM_015589.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.34

Genes affected

SAMD4A (HGNC:23023): (sterile alpha motif domain containing 4A) Sterile alpha motifs (SAMs) in proteins such as SAMD4A are part of an RNA-binding domain that functions as a posttranscriptional regulator by binding to an RNA sequence motif known as the Smaug recognition element, which was named after the Drosophila Smaug protein (Baez and Boccaccio, 2005 [PubMed 16221671]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08891812).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SAMD4A	NM_015589.6	c.1388C>T	p.Pro463Leu	missense_variant	7/13	ENST00000554335.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SAMD4A	ENST00000554335.6	c.1388C>T	p.Pro463Leu	missense_variant	7/13	5	NM_015589.6	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1403014 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 696200

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2021

The c.1388C>T (p.P463L) alteration is located in exon 6 (coding exon 6) of the SAMD4A gene. This alteration results from a C to T substitution at nucleotide position 1388, causing the proline (P) at amino acid position 463 to be replaced by a leucine (L). 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	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.034	T;.;.;T;.
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.23	N
LIST_S2	Uncertain	0.92	.;D;D;D;.
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.089	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;.;.;N;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-2.1	N;.;.;N;D
REVEL	Benign	0.047
Sift	Uncertain	0.0050	D;.;.;D;D
Sift4G	Uncertain	0.049	D;T;D;D;D
Polyphen		0.0	B;B;B;B;B
Vest4		0.15
MutPred		0.27		Loss of glycosylation at P463 (P = 0.0453);.;.;Loss of glycosylation at P463 (P = 0.0453);.;
MVP		0.043
MPC		0.53
ClinPred		0.24	T
GERP RS		4.4
Varity_R		0.065
gMVP		0.13

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: rs1053271797; hg19: chr14-55227090;