14-54760252-C-G

Variant names:

• chr14-54760252-C-G
• rs2038357312
• NM_015589.6:c.1268C>G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_015589.6(SAMD4A):​c.1268C>G​(p.Thr423Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,460,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 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: 0.0000048 (0 hom.)
• Consequence: SAMD4A NM_015589.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.00

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.047583997).
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SAMD4A	NM_015589.6	c.1268C>G	p.Thr423Ser	missense_variant	Exon 7 of 13	ENST00000554335.6	NP_056404.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SAMD4A	ENST00000554335.6	c.1268C>G	p.Thr423Ser	missense_variant	Exon 7 of 13	5	NM_015589.6	ENSP00000452535.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1460852 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 726748

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: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

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

Oct 10, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1268C>G (p.T423S) alteration is located in exon 6 (coding exon 6) of the SAMD4A gene. This alteration results from a C to G substitution at nucleotide position 1268, causing the threonine (T) at amino acid position 423 to be replaced by a serine (S). 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	0.066
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	10
DANN	Benign	0.48
DEOGEN2	Benign	0.0079	T;.;.;T;.
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.66	.;T;T;T;.
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.048	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.9	N;.;.;N;.
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.050	N;N;.;N;N
REVEL	Benign	0.11
Sift	Benign	0.41	T;T;.;T;T
Sift4G	Benign	1.0	T;T;T;T;T
Polyphen		0.0	B;B;B;B;B
Vest4		0.11
MutPred		0.16		Gain of glycosylation at T423 (P = 0.0635);.;.;Gain of glycosylation at T423 (P = 0.0635);.;
MVP		0.043
MPC		0.46
ClinPred		0.15	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.049
gMVP		0.21

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: rs2038357312; hg19: chr14-55226970;