8-8890241-T-C

Variant names:

• chr8-8890241-T-C
• NM_004225.3:c.2818A>G

Variant summary

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

The NM_004225.3(MFHAS1):​c.2818A>G​(p.Thr940Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MFHAS1 NM_004225.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.86
• Publications: 0 publications found

Genes affected

MFHAS1 (HGNC:16982): (multifunctional ROCO family signaling regulator 1) Identified in a human 8p amplicon, this gene is a potential oncogene whose expression is enhanced in some malignant fibrous histiocytomas (MFH). The primary structure of its product includes an ATP/GTP-binding site, three leucine zipper domains, and a leucine-rich tandem repeat, which are structural or functional elements for interactions among proteins related to the cell cycle, and which suggest that overexpression might be oncogenic with respect to MFH. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MFHAS1	NM_004225.3	c.2818A>G	p.Thr940Ala	missense_variant	Exon 1 of 3	ENST00000276282.7	NP_004216.2
MFHAS1	XM_047422419.1	c.2818A>G	p.Thr940Ala	missense_variant	Exon 1 of 3		XP_047278375.1
MFHAS1	XM_011543852.4	c.2818A>G	p.Thr940Ala	missense_variant	Exon 1 of 2		XP_011542154.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MFHAS1	ENST00000276282.7	c.2818A>G	p.Thr940Ala	missense_variant	Exon 1 of 3	1	NM_004225.3	ENSP00000276282.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 25, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2818A>G (p.T940A) alteration is located in exon 1 (coding exon 1) of the MFHAS1 gene. This alteration results from a A to G substitution at nucleotide position 2818, causing the threonine (T) at amino acid position 940 to be replaced by an alanine (A). 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	-0.061	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.059	T
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.0061	T
MetaRNN	Uncertain	0.51	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		5.9
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.10
Sift	Benign	0.085	T
Sift4G	Benign	0.065	T
Polyphen		0.88	P
Vest4		0.74
MutPred		0.21		Loss of glycosylation at T940 (P = 0.1862);
MVP		0.56
MPC		0.26
ClinPred		0.85	D
GERP RS		5.5
Varity_R		0.15
gMVP		0.53
Mutation Taster		=80/20	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

hg19: chr8-8747751;