chr9-136377646-G-A

Variant names:

• chr9-136377646-G-A
• rs139568835
• NM_003086.4:c.4181C>T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_003086.4(SNAPC4):​c.4181C>T​(p.Ser1394Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000751 in 1,592,982 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: 𝑓 0.00064 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00076 (0 hom.)
• Consequence: SNAPC4 NM_003086.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.24

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.011450857).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000643 (98/152310) while in subpopulation NFE AF= 0.00118 (80/68016). AF 95% confidence interval is 0.000968. There are 0 homozygotes in gnomad4. There are 38 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SNAPC4	NM_003086.4	c.4181C>T	p.Ser1394Leu	missense_variant	Exon 22 of 24	ENST00000684778.1	NP_003077.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SNAPC4	ENST00000684778.1	c.4181C>T	p.Ser1394Leu	missense_variant	Exon 22 of 24		NM_003086.4	ENSP00000510559.1

Frequencies

GnomAD3 genomes AF: 0.000644 AC: 98 AN: 152194 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00118

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000553 AC: 132 AN: 238606 Hom.: 0 AF XY: 0.000646 AC XY: 84 AN XY: 130104

Gnomad AFR exome AF: 0.0000640

Gnomad AMR exome AF: 0.000401

Gnomad ASJ exome AF: 0.000112

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000956

Gnomad NFE exome AF: 0.00102

Gnomad OTH exome AF: 0.000875

GnomAD4 exome AF: 0.000763 AC: 1099 AN: 1440672 Hom.: 0 Cov.: 42 AF XY: 0.000767 AC XY: 548 AN XY: 714132

Gnomad4 AFR exome AF: 0.000122

Gnomad4 AMR exome AF: 0.000425

Gnomad4 ASJ exome AF: 0.0000397

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.0000236

Gnomad4 FIN exome AF: 0.000116

Gnomad4 NFE exome AF: 0.000945

Gnomad4 OTH exome AF: 0.000455

GnomAD4 genome AF: 0.000643 AC: 98 AN: 152310 Hom.: 0 Cov.: 34 AF XY: 0.000510 AC XY: 38 AN XY: 74484

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00118

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000916 Hom.: 0

Bravo AF: 0.000695

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000932 AC: 8

ExAC AF: 0.000554 AC: 67

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

May 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4181C>T (p.S1394L) alteration is located in exon 21 (coding exon 21) of the SNAPC4 gene. This alteration results from a C to T substitution at nucleotide position 4181, causing the serine (S) at amino acid position 1394 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	0.079
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.8
DANN	Benign	0.96
DEOGEN2	Benign	0.0013	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.79	N
REVEL	Benign	0.044
Sift	Benign	0.18	T
Sift4G	Benign	0.25	T
Polyphen		0.0	B
Vest4		0.039
MVP		0.21
ClinPred		0.015	T
GERP RS		-1.7
Varity_R		0.033
gMVP		0.092

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: rs139568835; hg19: chr9-139272098;