chr4-76256518-A-T

Variant names:

• chr4-76256518-A-T
• rs1005224775
• NM_001136570.3:c.415A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001136570.3(FAM47E):​c.415A>T​(p.Ile139Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I139V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FAM47E NM_001136570.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.187
• Publications: 0 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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.047958255).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM47E	NM_001136570.3	c.415A>T	p.Ile139Leu	missense_variant	Exon 2 of 8	ENST00000424749.7	NP_001130042.1
FAM47E-STBD1	NM_001242939.2	c.415A>T	p.Ile139Leu	missense_variant	Exon 2 of 7		NP_001229868.1
FAM47E	NM_001242936.1	c.82-7186A>T		intron_variant	Intron 2 of 7		NP_001229865.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM47E	ENST00000424749.7	c.415A>T	p.Ile139Leu	missense_variant	Exon 2 of 8	5	NM_001136570.3	ENSP00000409423.2
FAM47E-STBD1	ENST00000515604.5	c.415A>T	p.Ile139Leu	missense_variant	Exon 2 of 7	2		ENSP00000422067.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.6
DANN	Benign	0.84
DEOGEN2	Benign	0.0049	T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.12	T;T
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.048	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.0	N;.
PhyloP100		-0.19
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-0.37	N;N
REVEL	Benign	0.016
Sift	Benign	0.23	T;T
Sift4G	Benign	0.33	T;T
Polyphen		0.0	B;.
Vest4		0.088
MutPred		0.58		Loss of methylation at K144 (P = 0.0543);Loss of methylation at K144 (P = 0.0543);
MVP		0.014
MPC		0.030
ClinPred		0.031	T
GERP RS		0.076
PromoterAI		-0.0068	Neutral
Varity_R		0.055
gMVP		0.28
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1005224775; hg19: chr4-77177671;