12-109396466-G-T

Variant names:

• chr12-109396466-G-T
• rs552213675
• NM_001101421.4:c.373G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001101421.4(MYO1H):​c.373G>T​(p.Ala125Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,672 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MYO1H NM_001101421.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.88

Genes affected

MYO1H (HGNC:13879): (myosin IH) Predicted to enable actin filament binding activity and microfilament motor activity. Predicted to be involved in actin filament organization and vesicle transport along actin filament. Predicted to be part of myosin complex. Predicted to be active in several cellular components, including actin cytoskeleton; microvillus; and vesicle. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 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
MYO1H	NM_001101421.4	c.373G>T	p.Ala125Ser	missense_variant	Exon 4 of 32	ENST00000310903.10	NP_001094891.4
MYO1H	XM_011538223.3	c.325G>T	p.Ala109Ser	missense_variant	Exon 5 of 34		XP_011536525.1
MYO1H	XM_047428738.1	c.325G>T	p.Ala109Ser	missense_variant	Exon 3 of 31		XP_047284694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO1H	ENST00000310903.10	c.373G>T	p.Ala125Ser	missense_variant	Exon 4 of 32	5	NM_001101421.4	ENSP00000439182.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461672 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727110

Gnomad4 AFR exome AF: 0.0000597

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.325G>T (p.A109S) alteration is located in exon 3 (coding exon 3) of the MYO1H gene. This alteration results from a G to T substitution at nucleotide position 325, causing the alanine (A) at amino acid position 109 to be replaced by a serine (S). 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
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	22
DANN	Uncertain	0.99
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.011	T
MetaRNN	Uncertain	0.70	D;D
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	1.5	.;L
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.6	.;N
REVEL	Uncertain	0.38
Sift	Benign	0.35	.;T
Sift4G	Benign	0.44	T;T
Vest4		0.66
MutPred		0.76		.;Gain of catalytic residue at S107 (P = 0);
MVP		0.77
MPC		0.11
ClinPred		0.82	D
GERP RS		4.8
gMVP		0.70

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: rs552213675; hg19: chr12-109834271;