X-34130361-C-T

Variant names:

• chrX-34130361-C-T
• rs766609741
• NM_203408.4:c.1918G>A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_203408.4(FAM47A):​c.1918G>A​(p.Glu640Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000364 in 1,098,221 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000036 (0 hom. 2 hem.)
• Consequence: FAM47A NM_203408.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.24

Genes affected

FAM47A (HGNC:29962): (family with sequence similarity 47 member A)

ENSG00000233928 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.084884405).
• BS2: High Hemizygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM47A	NM_203408.4	c.1918G>A	p.Glu640Lys	missense_variant	Exon 1 of 1	ENST00000346193.5	NP_981953.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM47A	ENST00000346193.5	c.1918G>A	p.Glu640Lys	missense_variant	Exon 1 of 1	6	NM_203408.4	ENSP00000345029.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.00000549 AC: 1 AN: 182105 Hom.: 0 AF XY: 0.0000148 AC XY: 1 AN XY: 67533

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: 0.00

Gnomad OTH exome AF: 0.000224

GnomAD4 exome AF: 0.00000364 AC: 4 AN: 1098221 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 2 AN XY: 363579

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: 0.00000475

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000756

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 24, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1918G>A (p.E640K) alteration is located in exon 1 (coding exon 1) of the FAM47A gene. This alteration results from a G to A substitution at nucleotide position 1918, causing the glutamic acid (E) at amino acid position 640 to be replaced by a lysine (K). 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	0.16
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.023
DANN	Benign	0.31
DEOGEN2	Benign	0.019	T;.
FATHMM_MKL	Benign	0.00077	N
LIST_S2	Benign	0.42	T;T
M_CAP	Benign	0.0016	T
MetaRNN	Benign	0.085	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.9	N;.
REVEL	Benign	0.014
Sift	Benign	0.083	T;.
Sift4G	Benign	0.12	T;T
Polyphen		0.19	B;.
Vest4		0.069
MutPred		0.27		Gain of MoRF binding (P = 0.0029);.;
MVP		0.043
MPC		0.25
ClinPred		0.040	T
GERP RS		-0.87
Varity_R		0.068
gMVP		0.064

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: rs766609741; hg19: chrX-34148478;