11-126250722-G-A

Variant names:

• chr11-126250722-G-A
• NM_024556.4:c.556G>A

Variant summary

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

The NM_024556.4(FAM118B):​c.556G>A​(p.Asp186Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,586 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: FAM118B NM_024556.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.46
• Publications: 0 publications found

Genes affected

FAM118B (HGNC:26110): (family with sequence similarity 118 member B) Enables identical protein binding activity. Predicted to be involved in Cajal body organization. Predicted to be located in Cajal body. [provided by Alliance of Genome Resources, Apr 2022]

SRPRA (HGNC:11307): (SRP receptor subunit alpha) The gene encodes a subunit of the endoplasmic reticulum signal recognition particle receptor that, in conjunction with the signal recognition particle, is involved in the targeting and translocation of signal sequence tagged secretory and membrane proteins across the endoplasmic reticulum. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2010]

SRPRA Gene-Disease associations (from GenCC):

• Shwachman-Diamond syndrome

  Inheritance: AD Classification: MODERATE Submitted by: PanelApp Australia
• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

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_024556.4. 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
	FAM118B	NM_024556.4	MANE Select	c.556G>A	p.Asp186Asn	missense	Exon 5 of 9	NP_078832.1	Q9BPY3
	FAM118B	NM_001439324.1		c.556G>A	p.Asp186Asn	missense	Exon 4 of 8	NP_001426253.1
	FAM118B	NM_001330446.2		c.556G>A	p.Asp186Asn	missense	Exon 5 of 9	NP_001317375.1	J3KP39

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM118B	ENST00000533050.6	TSL:1 MANE Select	c.556G>A	p.Asp186Asn	missense	Exon 5 of 9	ENSP00000433343.1	Q9BPY3
	FAM118B	ENST00000891485.1		c.556G>A	p.Asp186Asn	missense	Exon 5 of 10	ENSP00000561544.1
	FAM118B	ENST00000891481.1		c.568G>A	p.Asp190Asn	missense	Exon 5 of 9	ENSP00000561540.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459586 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726080

African (AFR) AF: 0.00 AC: 0 AN: 33402

American (AMR) AF: 0.00 AC: 0 AN: 44620

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.00 AC: 0 AN: 85980

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1110346

Other (OTH) AF: 0.00 AC: 0 AN: 60318

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.089	T
BayesDel_noAF	Benign	-0.37
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.046	T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.0093	T
MetaRNN	Uncertain	0.59	D
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.63	N
PhyloP100		9.5
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.30
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.66
MutPred		0.59		Loss of phosphorylation at T185 (P = 0.0933)
MVP		0.80
MPC		0.76
ClinPred		0.95	D
GERP RS		6.2
Varity_R		0.51
gMVP		0.62
Mutation Taster		=24/76	disease causing

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

hg19: chr11-126120617;