9-136377990-C-G

Variant summary

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

The NM_003086.4(SNAPC4):c.3837G>C(p.Glu1279Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000414 in 1,450,634 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: SNAPC4 NM_003086.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.102

Genes affected

SNAPC4 (HGNC:11137): (small nuclear RNA activating complex polypeptide 4) This gene encodes the largest subunit of the small nuclear RNA-activating protein (SNAP) complex. The encoded protein contains a Myb DNA-binding domain, and is essential for RNA polymerase II and III polymerase transcription from small nuclear RNA promoters. A mutation in this gene is associated with ankylosing spondylitis. [provided by RefSeq, Jul 2016]

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=0.09556511).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SNAPC4	NM_003086.4	c.3837G>C	p.Glu1279Asp	missense_variant	22/24	ENST00000684778.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SNAPC4	ENST00000684778.1	c.3837G>C	p.Glu1279Asp	missense_variant	22/24		NM_003086.4	P1
SNAPC4	ENST00000298532.2	c.3837G>C	p.Glu1279Asp	missense_variant	21/23	1		P1
SNAPC4	ENST00000637388.2	c.3837G>C	p.Glu1279Asp	missense_variant	22/24	5		P1
SNAPC4	ENST00000689006.1	c.*3050G>C		3_prime_UTR_variant, NMD_transcript_variant	22/24

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000451 AC: 1 AN: 221760 Hom.: 0 AF XY: 0.00000811 AC XY: 1 AN XY: 123376

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000104

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000414 AC: 6 AN: 1450634 Hom.: 0 Cov.: 42 AF XY: 0.00000416 AC XY: 3 AN XY: 720802

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: 0.00000542

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ExAC AF: 0.00000854 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 17, 2022

The c.3837G>C (p.E1279D) alteration is located in exon 21 (coding exon 21) of the SNAPC4 gene. This alteration results from a G to C substitution at nucleotide position 3837, causing the glutamic acid (E) at amino acid position 1279 to be replaced by an aspartic acid (D). 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	0.20
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	16
Dann	Uncertain	0.99
DEOGEN2	Benign	0.016	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.096	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.029
Sift	Benign	0.040	D
Sift4G	Benign	0.19	T
Polyphen		0.33	B
Vest4		0.20
MutPred		0.089		Gain of MoRF binding (P = 0.2353);
MVP		0.35
ClinPred		0.079	T
GERP RS		2.5
Varity_R		0.070
gMVP		0.20

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: rs754838345; hg19: chr9-139272442;