NM_001136570.3:c.518C>T

Variant names:

• chr4-76263801-C-T
• rs982121618
• NM_001136570.3:c.518C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001136570.3(FAM47E):​c.518C>T​(p.Thr173Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000367 in 1,551,350 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000039 (0 hom.)
• Consequence: FAM47E NM_001136570.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.168
• Publications: 1 publications found

Genes affected

FAM47E (HGNC:34343): (family with sequence similarity 47 member E) Enables enzyme activator activity. Involved in positive regulation of histone methylation and protein localization to chromatin. Located in chromatin; cytoplasm; and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

FAM47E-STBD1 (HGNC:44667): (FAM47E-STBD1 readthrough) This locus represents naturally occurring read-through transcription between the neighboring FAM47E (family with sequence similarity 47, member E) and STBD1 (starch binding domain 1) genes on chromosome 4. The read-through transcript encodes a protein that shares sequence identity with the upstream gene product but its C-terminal region is distinct due to frameshifts relative to the downstream gene. [provided by RefSeq, Jul 2011]

ENSG00000287401 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15519595).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM47E	NM_001136570.3	c.518C>T	p.Thr173Met	missense_variant	Exon 3 of 8	ENST00000424749.7	NP_001130042.1
FAM47E-STBD1	NM_001242939.2	c.518C>T	p.Thr173Met	missense_variant	Exon 3 of 7		NP_001229868.1
FAM47E	NM_001242936.1	c.179C>T	p.Thr60Met	missense_variant	Exon 3 of 8		NP_001229865.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM47E	ENST00000424749.7	c.518C>T	p.Thr173Met	missense_variant	Exon 3 of 8	5	NM_001136570.3	ENSP00000409423.2
FAM47E-STBD1	ENST00000515604.5	c.518C>T	p.Thr173Met	missense_variant	Exon 3 of 7	2		ENSP00000422067.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000127 AC: 2 AN: 157022 AF XY: 0.0000120

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000386 AC: 54 AN: 1399214 Hom.: 0 Cov.: 30 AF XY: 0.0000391 AC XY: 27 AN XY: 690114

African (AFR) AF: 0.00 AC: 0 AN: 31576

American (AMR) AF: 0.00 AC: 0 AN: 35698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25178

East Asian (EAS) AF: 0.00 AC: 0 AN: 35736

South Asian (SAS) AF: 0.000227 AC: 18 AN: 79224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49294

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 0.0000324 AC: 35 AN: 1078810

Other (OTH) AF: 0.0000172 AC: 1 AN: 58004

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152136 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74304

African (AFR) AF: 0.00 AC: 0 AN: 41428

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 09, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.518C>T (p.T173M) alteration is located in exon 3 (coding exon 3) of the FAM47E gene. This alteration results from a C to T substitution at nucleotide position 518, causing the threonine (T) at amino acid position 173 to be replaced by a methionine (M). 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	0.10
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	12
DANN	Uncertain	1.0
DEOGEN2	Benign	0.023	.;.;.;.;T;.
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.81	T;T;T;T;T;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.16	T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.8	.;.;.;.;L;.
PhyloP100		-0.17
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-3.5	D;D;.;.;D;D
REVEL	Benign	0.056
Sift	Uncertain	0.0030	D;D;.;.;D;D
Sift4G	Uncertain	0.046	D;D;.;.;T;D
Polyphen		0.99	D;D;.;.;P;.
Vest4		0.089
MVP		0.24
MPC		0.052
ClinPred		0.29	T
GERP RS		1.5
PromoterAI		-0.016	Neutral
Varity_R		0.088
gMVP		0.20
Mutation Taster		=93/7	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: rs982121618; hg19: chr4-77184954; COSMIC: COSV100369055; COSMIC: COSV100369055;