9-131275957-C-T

Variant names:

• chr9-131275957-C-T
• rs915607693
• NM_033387.4:c.223G>A

Variant summary

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

The NM_001400586.1(FAM78A):​c.-367G>A variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.000000684 in 1,461,198 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: 6.8e-7 (0 hom.)
• Consequence: FAM78A NM_001400586.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.85
• Publications: 0 publications found

Genes affected

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

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_001400586.1. 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.223G>A	p.Val75Met	missense	Exon 1 of 2	NP_203745.2	Q5JUQ0
	FAM78A	NM_001400586.1		c.-367G>A		5_prime_UTR_premature_start_codon_gain	Exon 2 of 4	NP_001387515.1
	FAM78A	NM_001399459.1		c.223G>A	p.Val75Met	missense	Exon 2 of 3	NP_001386388.1	Q5JUQ0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM78A	ENST00000372271.4	TSL:1 MANE Select	c.223G>A	p.Val75Met	missense	Exon 1 of 2	ENSP00000361345.3	Q5JUQ0
	FAM78A	ENST00000704762.1		c.223G>A	p.Val75Met	missense	Exon 2 of 3	ENSP00000516028.1	Q5JUQ0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461198 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726896

⚠️ 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: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52802

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111988

Other (OTH) AF: 0.00 AC: 0 AN: 60382

⚠️ 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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	0.81
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.011	T
MetaRNN	Uncertain	0.63	D
MetaSVM	Benign	-0.65	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		3.8
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.23
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.94	P
Vest4		0.55
MutPred		0.76		Loss of sheet (P = 0.0181)
MVP		0.12
MPC		1.3
ClinPred		0.94	D
GERP RS		4.6
Varity_R		0.31
gMVP		0.65
Mutation Taster		=90/10	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: rs915607693; hg19: chr9-134151344;