X-150470178-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_005491.5(MAMLD1):c.605C>T(p.Thr202Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00146 in 1,209,859 control chromosomes in the GnomAD database, including 1 homozygotes. There are 548 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. T202T) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00096 (0 hom., 31 hem., cov: 23)
  • Exomes 𝑓: 0.0015 (1 hom. 517 hem.)
• Consequence: MAMLD1 NM_005491.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: 1.54

Genes affected

MAMLD1 (HGNC:2568): (mastermind like domain containing 1) This gene encodes a mastermind-like domain containing protein. This protein may function as a transcriptional co-activator. Mutations in this gene are the cause of X-linked hypospadias type 2. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Apr 2010]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008919567).
• BP6: Variant X-150470178-C-T is Benign according to our data. Variant chrX-150470178-C-T is described in ClinVar as [Benign]. Clinvar id is 726221.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-150470178-C-T is described in Lovd as [Benign]. Variant chrX-150470178-C-T is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAd at 31 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAMLD1	NM_005491.5	c.605C>T	p.Thr202Met	missense_variant	4/8	ENST00000370401.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAMLD1	ENST00000370401.7	c.605C>T	p.Thr202Met	missense_variant	4/8	5	NM_005491.5	A2

Frequencies

GnomAD3 genomes AF: 0.000959 AC: 107 AN: 111599 Hom.: 0 Cov.: 23 AF XY: 0.000918 AC XY: 31 AN XY: 33787

Gnomad AFR AF: 0.0000980

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000947

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000376

Gnomad FIN AF: 0.00166

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00173

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00112 AC: 205 AN: 183456 Hom.: 0 AF XY: 0.00112 AC XY: 76 AN XY: 67898

Gnomad AFR exome AF: 0.0000760

Gnomad AMR exome AF: 0.000328

Gnomad ASJ exome AF: 0.000534

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00325

Gnomad NFE exome AF: 0.00167

Gnomad OTH exome AF: 0.000441

GnomAD4 exome AF: 0.00151 AC: 1654 AN: 1098206 Hom.: 1 Cov.: 34 AF XY: 0.00142 AC XY: 517 AN XY: 363562

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.000312

Gnomad4 ASJ exome AF: 0.000413

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000369

Gnomad4 FIN exome AF: 0.00323

Gnomad4 NFE exome AF: 0.00171

Gnomad4 OTH exome AF: 0.00130

GnomAD4 genome AF: 0.000958 AC: 107 AN: 111653 Hom.: 0 Cov.: 23 AF XY: 0.000916 AC XY: 31 AN XY: 33851

Gnomad4 AFR AF: 0.0000978

Gnomad4 AMR AF: 0.0000945

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000377

Gnomad4 FIN AF: 0.00166

Gnomad4 NFE AF: 0.00173

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00212 Hom.: 18

Bravo AF: 0.000695

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00173 AC: 5

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00104 AC: 7

ExAC AF: 0.00137 AC: 166

EpiCase AF: 0.00136

EpiControl AF: 0.00219

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 02, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.050	T;.;.;T
FATHMM_MKL	Benign	0.65	D
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.0089	T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.1	L;.;.;L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.2	N;N;N;N
REVEL	Benign	0.16
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Uncertain	0.019	D;D;D;D
Polyphen		0.99	D;D;D;D
Vest4		0.14
MVP		0.25
MPC		0.60
ClinPred		0.058	T
GERP RS		1.5
Varity_R		0.071
gMVP		0.17

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: rs146555522; hg19: chrX-149638450; COSMIC: COSV53379823; COSMIC: COSV53379823;