19-53874169-T-C

Variant names:

• chr19-53874169-T-C
• rs748605110
• NM_138373.5:c.640T>C

Variant summary

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

The NM_138373.5(MYADM):​c.640T>C​(p.Phe214Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,626 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: MYADM NM_138373.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.19

Genes affected

MYADM (HGNC:7544): (myeloid associated differentiation marker) Involved in several processes, including negative regulation of heterotypic cell-cell adhesion; negative regulation of macromolecule metabolic process; and negative regulation of protein kinase C signaling. Located in several cellular components, including cortical actin cytoskeleton; membrane raft; and ruffle. [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
MYADM	NM_138373.5	c.640T>C	p.Phe214Leu	missense_variant	Exon 3 of 3	ENST00000391770.9	NP_612382.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYADM	ENST00000391770.9	c.640T>C	p.Phe214Leu	missense_variant	Exon 3 of 3	1	NM_138373.5	ENSP00000375650.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000637 AC: 16 AN: 251134 Hom.: 1 AF XY: 0.0000663 AC XY: 9 AN XY: 135720

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000870

Gnomad SAS 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: 0.00000342 AC: 5 AN: 1461626 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727122

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

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.: 32

Bravo AF: 0.0000113

ExAC AF: 0.0000741 AC: 9

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 26, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.640T>C (p.F214L) alteration is located in exon 2 (coding exon 1) of the MYADM gene. This alteration results from a T to C substitution at nucleotide position 640, causing the phenylalanine (F) at amino acid position 214 to be replaced by a leucine (L). 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	Pathogenic	0.99
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T;T;.;T;T;T;T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.83	.;.;T;T;.;.;.
M_CAP	Benign	0.065	D
MetaRNN	Uncertain	0.66	D;D;D;D;D;D;D
MetaSVM	Benign	-0.75	T
MutationAssessor	Uncertain	2.8	.;M;.;M;M;M;M
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-5.8	D;D;D;D;D;D;D
REVEL	Uncertain	0.43
Sift	Pathogenic	0.0	D;D;D;D;D;D;D
Sift4G	Uncertain	0.023	D;D;D;D;D;D;D
Polyphen		0.95	.;P;.;P;P;P;P
Vest4		0.87, 0.89
MutPred		0.74		Gain of catalytic residue at C213 (P = 0.7144);Gain of catalytic residue at C213 (P = 0.7144);Gain of catalytic residue at C213 (P = 0.7144);Gain of catalytic residue at C213 (P = 0.7144);Gain of catalytic residue at C213 (P = 0.7144);Gain of catalytic residue at C213 (P = 0.7144);Gain of catalytic residue at C213 (P = 0.7144);
MVP		0.37
MPC		1.1
ClinPred		0.78	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.83

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: rs748605110; hg19: chr19-54377423;