rs41313406

Variant names:

• chrX-150470648-C-T
• rs41313406
• NM_005491.5:c.1075C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005491.5(MAMLD1):​c.1075C>T​(p.Pro359Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.11 in 1,209,970 control chromosomes in the GnomAD database, including 5,619 homozygotes. There are 42,894 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.082 (408 hom., 2550 hem., cov: 23)
  • Exomes 𝑓: 0.11 (5211 hom. 40344 hem.)
• Consequence: MAMLD1 NM_005491.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.09
• Publications: 16 publications found

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]

MAMLD1 Gene-Disease associations (from GenCC):

• hypospadias 2, X-linked

  Inheritance: XL Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017882288).
• BP6: Variant X-150470648-C-T is Benign according to our data. Variant chrX-150470648-C-T is described in ClinVar as Benign. ClinVar VariationId is 1542510.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005491.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAMLD1	NM_005491.5	MANE Select	c.1075C>T	p.Pro359Ser	missense	Exon 4 of 8	NP_005482.2
	MAMLD1	NM_001400512.1		c.1075C>T	p.Pro359Ser	missense	Exon 4 of 6	NP_001387441.1
	MAMLD1	NM_001177465.3		c.1000C>T	p.Pro334Ser	missense	Exon 3 of 5	NP_001170936.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAMLD1	ENST00000370401.7	TSL:5 MANE Select	c.1075C>T	p.Pro359Ser	missense	Exon 4 of 8	ENSP00000359428.2
	MAMLD1	ENST00000426613.5	TSL:1	c.1000C>T	p.Pro334Ser	missense	Exon 4 of 8	ENSP00000397438.2
	MAMLD1	ENST00000682016.1		c.1075C>T	p.Pro359Ser	missense	Exon 5 of 7	ENSP00000507991.1

Frequencies

GnomAD3 genomes AF: 0.0825 AC: 9227 AN: 111791 Hom.: 408 Cov.: 23

Gnomad AFR AF: 0.0149

Gnomad AMI AF: 0.151

Gnomad AMR AF: 0.0765

Gnomad ASJ AF: 0.126

Gnomad EAS AF: 0.000280

Gnomad SAS AF: 0.0205

Gnomad FIN AF: 0.105

Gnomad MID AF: 0.106

Gnomad NFE AF: 0.126

Gnomad OTH AF: 0.0885

GnomAD2 exomes AF: 0.0829 AC: 15030 AN: 181336 AF XY: 0.0851

Gnomad AFR exome AF: 0.0136

Gnomad AMR exome AF: 0.0476

Gnomad ASJ exome AF: 0.133

Gnomad EAS exome AF: 0.000289

Gnomad FIN exome AF: 0.114

Gnomad NFE exome AF: 0.121

Gnomad OTH exome AF: 0.0967

GnomAD4 exome AF: 0.113 AC: 123680 AN: 1098127 Hom.: 5211 Cov.: 35 AF XY: 0.111 AC XY: 40344 AN XY: 363487

African (AFR) AF: 0.0147 AC: 388 AN: 26403

American (AMR) AF: 0.0519 AC: 1828 AN: 35202

Ashkenazi Jewish (ASJ) AF: 0.135 AC: 2614 AN: 19386

East Asian (EAS) AF: 0.000232 AC: 7 AN: 30206

South Asian (SAS) AF: 0.0354 AC: 1916 AN: 54147

European-Finnish (FIN) AF: 0.116 AC: 4679 AN: 40467

Middle Eastern (MID) AF: 0.0948 AC: 392 AN: 4136

European-Non Finnish (NFE) AF: 0.127 AC: 107105 AN: 842086

Other (OTH) AF: 0.103 AC: 4751 AN: 46094

GnomAD4 genome AF: 0.0825 AC: 9222 AN: 111843 Hom.: 408 Cov.: 23 AF XY: 0.0749 AC XY: 2550 AN XY: 34031

African (AFR) AF: 0.0149 AC: 459 AN: 30833

American (AMR) AF: 0.0763 AC: 813 AN: 10660

Ashkenazi Jewish (ASJ) AF: 0.126 AC: 332 AN: 2642

East Asian (EAS) AF: 0.000281 AC: 1 AN: 3558

South Asian (SAS) AF: 0.0210 AC: 56 AN: 2668

European-Finnish (FIN) AF: 0.105 AC: 638 AN: 6068

Middle Eastern (MID) AF: 0.112 AC: 24 AN: 215

European-Non Finnish (NFE) AF: 0.126 AC: 6666 AN: 53002

Other (OTH) AF: 0.0861 AC: 131 AN: 1521

Alfa AF: 0.111 Hom.: 5337

Bravo AF: 0.0788

ESP6500AA AF: 0.0177 AC: 68

ESP6500EA AF: 0.126 AC: 846

ExAC AF: 0.0841 AC: 10215

EpiCase AF: 0.125

EpiControl AF: 0.123

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	11
DANN	Uncertain	0.98
DEOGEN2	Benign	0.049	T
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	2.0	M
PhyloP100		1.1
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.12
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.44	T
Polyphen		0.78	P
Vest4		0.083
MPC		0.35
ClinPred		0.023	T
GERP RS		0.28
Varity_R		0.14
gMVP		0.47
Mutation Taster		=99/1	polymorphism (auto)

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

dbSNP: rs41313406; hg19: chrX-149638920; COSMIC: COSV53375005; COSMIC: COSV53375005;