14-54776457-G-C

Variant names:

• chr14-54776457-G-C
• rs1249869962
• NM_015589.6:c.1961G>C

Variant summary

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

The NM_015589.6(SAMD4A):​c.1961G>C​(p.Ser654Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,443,046 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S654N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SAMD4A NM_015589.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.60
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015589.6. 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
	SAMD4A	NM_015589.6	MANE Select	c.1961G>C	p.Ser654Thr	missense	Exon 11 of 13	NP_056404.4	Q9UPU9-1
	SAMD4A	NM_001161576.2		c.1697G>C	p.Ser566Thr	missense	Exon 9 of 11	NP_001155048.2	Q9UPU9-3
	SAMD4A	NM_001161577.2		c.734G>C	p.Ser245Thr	missense	Exon 6 of 9	NP_001155049.1	G3V2R1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SAMD4A	ENST00000554335.6	TSL:5 MANE Select	c.1961G>C	p.Ser654Thr	missense	Exon 11 of 13	ENSP00000452535.1	Q9UPU9-1
	SAMD4A	ENST00000251091.9	TSL:1	c.1697G>C	p.Ser566Thr	missense	Exon 9 of 11	ENSP00000251091.5	Q9UPU9-3
	SAMD4A	ENST00000555192.1	TSL:1	c.734G>C	p.Ser245Thr	missense	Exon 6 of 9	ENSP00000450808.1	G3V2R1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1443046 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 717558

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32282

American (AMR) AF: 0.00 AC: 0 AN: 41812

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25834

East Asian (EAS) AF: 0.00 AC: 0 AN: 37436

South Asian (SAS) AF: 0.00 AC: 0 AN: 83244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53134

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1103820

Other (OTH) AF: 0.00 AC: 0 AN: 59750

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.088	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.0090	T
MetaRNN	Uncertain	0.46	T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	1.7	L
PhyloP100		9.6
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.25
Sift	Uncertain	0.028	D
Sift4G	Benign	0.23	T
Polyphen		0.99	D
Vest4		0.62
MutPred		0.13		Loss of phosphorylation at S654 (P = 0.0468)
MVP		0.23
MPC		1.4
ClinPred		0.87	D
GERP RS		5.4
Varity_R		0.41
gMVP		0.65
Mutation Taster		=58/42	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: rs1249869962; hg19: chr14-55243175;