chr9-131261298-C-T

Variant names:

• chr9-131261298-C-T
• rs1235105622
• NM_033387.4:c.376G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_033387.4(FAM78A):​c.376G>A​(p.Asp126Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,452,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: FAM78A NM_033387.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.84
• Publications: 2 publications found

Genes affected

FAM78A (HGNC:25465): (family with sequence similarity 78 member A)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.882

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033387.4. 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
	FAM78A	NM_033387.4	MANE Select	c.376G>A	p.Asp126Asn	missense	Exon 2 of 2	NP_203745.2	Q5JUQ0
	FAM78A	NM_001399459.1		c.376G>A	p.Asp126Asn	missense	Exon 3 of 3	NP_001386388.1	Q5JUQ0
	FAM78A	NM_001400581.1		c.376G>A	p.Asp126Asn	missense	Exon 3 of 3	NP_001387510.1	Q5JUQ0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM78A	ENST00000372271.4	TSL:1 MANE Select	c.376G>A	p.Asp126Asn	missense	Exon 2 of 2	ENSP00000361345.3	Q5JUQ0
	FAM78A	ENST00000372269.7	TSL:1	c.367G>A	p.Asp123Asn	missense	Exon 4 of 4	ENSP00000361343.3	Q5JUQ2
	FAM78A	ENST00000704762.1		c.376G>A	p.Asp126Asn	missense	Exon 3 of 3	ENSP00000516028.1	Q5JUQ0

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000412 AC: 1 AN: 242432 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000897

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1452136 Hom.: 0 Cov.: 34 AF XY: 0.00000277 AC XY: 2 AN XY: 722636

African (AFR) AF: 0.00 AC: 0 AN: 33444

American (AMR) AF: 0.00 AC: 0 AN: 44562

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25986

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86188

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45044

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111190

Other (OTH) AF: 0.00 AC: 0 AN: 60272

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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	Pathogenic	1.0
BayesDel_addAF	Benign	0.0012	T
BayesDel_noAF	Benign	-0.24
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.014	T
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		7.8
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.1	D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.017	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.81		Loss of catalytic residue at D126 (P = 0.0938)
MVP		0.24
MPC		1.8
ClinPred		0.94	D
GERP RS		4.8
Varity_R		0.53
gMVP		0.82
Mutation Taster		=53/47	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: rs1235105622; hg19: chr9-134136685; COSMIC: COSV55993172;